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Building a Future Free of Age-Related Disease

Lung branches

A Look at Idiopathic Pulmonary Fibrosis

A new review published in the American Journal of Respiratory Cell and Molecular Biology discusses the causes of, and potential treatments for, idiopathic pulmonary fibrosis (IPF).

Fibrosis, but not focused on fibroblasts

In the lungs, the trachea (airway) breaks out into a tree-like system of nodes. Each branch ends in alveoli, which are responsible for gas exchange between the air and the bloodstream. This is where the distal epithelium resides, and it has two types of cells: AEC1 and AEC2. AEC1 cells are involved in the gas exchange itself, as their thin membranes allow the entry of oxygen and the release of carbon dioxide. AEC2 cells are cubic in shape, and they secrete a surfactant that prevents the alveoli from collapsing. Furthermore, they are able to self-renew and differentiate into AEC1 cells, so they function like stem cells [1].

The direct cause of the fibrosis in IPF is fibroblasts. Previous research has shown that cellular senescence is linked to IPF, and one paper has shown that the senescence-associated secretory phenotype (SASP) is linked to aberrantly activated fibroblasts [2].

However, this review cites research showing that IPF begins with the distal epithelium, not the fibroblasts, and that targeting the disease here may be sufficient to slow or reverse it [3]. The researchers portray this as wound healing gone wrong, and in addition to genetic predispositions for the disease, they cite multiple aspects of aging that may contribute to IPF.

Extracellular matrix dysfunction

The accumulation of cross-links in the extracellular matrix has been associated with multiple aspects of aging, including arterial stiffness. Here, the reviewers cite research showing that the extracellular matrix of IPF patients affects fibroblasts more strongly than where the fibroblasts themselves originated [4]. The lungs of IPF patients are less elastic than the lungs of people without this disease, and one experiment showed that stretching IPF tissue causes the release of TGF-beta 1 [5], a compound that has positive effects in normal concentrations but is known to cause fibrosis in excess.

Cellular senescence and apoptosis

Research has shown that fibroblasts are not the only cells whose senescence implicates IPF; senescent distal epithelial cells are involved as well. In particular, the senescence marker and transcription factor p53 is directly linked to the progression of the disease, as it drives aberrant cellular behavior in AEC2 cells [6].

The reviewers also suggest that premature or aberrant induction of apoptosis (cell death) pathways might also be partially responsible for the disease. One mouse experiment reduced GSTP, a chemical known to activate apoptosis, and the effects on IPF were positive [7].

Loss of proteostasis and mitochondrial dysfunction

One cause of IPF may be unfolded or misfolded proteins, which is one of the hallmarks of aging: the loss of proteostasis. In the context of IPF, the loss of proteostasis places stress on the endoplasmic reticulum (ER), the part of the cell that is responsible for protein maintenance. In one mouse experiment, the unfolded protein response was triggered in the ER of AEC2 cells, which led directly to fibrosis [8]. The reviewers also cite multiple research papers in which mutations to the genes responsible for the surfactant proteins of AEC2 cells are shown to drive the development of IPF.

Mitochondrial dysfunction, another hallmark of aging, was also cited as a cause of ER stress and, ultimately, IPF. Specifically, the reviewers highlight the lack of autophagy. In autophagy, cells consume their own organelles, eating parts of themselves as part of survival and maintenance. While too much autophagy can lead to apoptosis, not enough can cause dysfunctional mitochondria to proliferate, and these dysfunctional mitochondria are linked to IPF [9].

Potential treatments

The reviewers first point out that there is a strategy that has never been shown to work: directly targeting the fibroblasts themselves. Attempting to treat IPF with anti-inflammatories has also returned generally negative results.

They then go on to show the difficulties inherent in targeting signaling pathways, particularly in the case of IPF, as the number of interlinked pathways makes it difficult to create a targeted drug. There are a great number of clinical trials aimed at these signaling pathways in IPF, although none of them have yet surpassed Phase 2.

The reviewers hold that, on top of a lack of drugs that target the distal epithelium, there is an unmet need for more advanced approaches to IPF, including stem cell therapies, gene therapies, and other treatments that go beyond simple pharmacology, such as nanoparticles and nanotechnology-based antibodies.

Abstract

Idiopathic pulmonary fibrosis is a fatal interstitial lung disease with limited therapeutic options. Current evidence suggests that IPF may be initiated by repeated epithelial injury in the distal lung followed by abnormal wound healing responses which occur due to intrinsic and extrinsic factors. Mechanisms contributing to chronic damage of the alveolar epithelium in IPF include dysregulated cellular processes such as apoptosis, senescence, abnormal activation of developmental pathways, aging, as well as genetic mutations. Therefore, targeting the regenerative capacity of the lung epithelium is an attractive approach in the development of novel therapies for IPF. Endogenous lung regeneration is a complex process involving coordinated cross-talk between multiple cell types and re-establishment of a normal extracellular matrix environment. This review will describe the current knowledge of reparative epithelial progenitor cells in the alveolar region of the lung and discuss potential novel therapeutic approaches for IPF focusing on endogenous alveolar repair. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Conclusion

This review is extremely in-depth, and it cites multiple avenues of research that have discovered many different biological problems that are linked to IPF. This raises the concern that IPF may be fundamentally caused by multiple upstream factors, so there cannot be a single treatment to cure it, just as there is no one cure for all cancers. However, as research progresses and we learn more about how to deal with this frustrating and deadly disease, we may be able to restore AEC2 populations, decrease fibrosis, and, ultimately, allow people to breathe easier.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, Randell SH, Noble PW, Hogan BLM. Type 2 alveolar cells are stem cells in adult lung. The Journal of clinical investigation 2013; 123: 3025-3036.

[2] Álvarez, D., Cárdenes, N., Sellarés, J., Bueno, M., Corey, C., Hanumanthu, V. S., … & Rojas, M. (2017). IPF lung fibroblasts have a senescent phenotype. American Journal of Physiology-Lung Cellular and Molecular Physiology, 313(6), L1164-L1173.

[3] Yuan T, Volckaert T, Redente EF, Hopkins S, Klinkhammer K, Wasnick R, Chao C-M, Yuan J, Zhang J-S, Yao C, Majka S, Stripp BR, Günther A, Riches DWH, Bellusci S, Thannickal VJ, De Langhe SP. FGF10-FGFR2B Signaling Generates Basal Cells and Drives Alveolar Epithelial Regeneration by Bronchial Epithelial Stem Cells after Lung Injury. Stem Cell Reports 2019; 12: 1041-1055.

[4] Parker MW, Rossi D, Peterson M, Smith K, Sikström K, White ES, Connett JE, Henke CA, Larsson O, Bitterman PB. Fibrotic extracellular matrix activates a profibrotic positive feedback loop. The Journal of clinical investigation 2014; 124: 1622-1635.

[5] Froese AR, Shimbori C, Bellaye P-S, Inman M, Obex S, Fatima S, Jenkins G, Gauldie J, Ask K, Kolb M. Stretch-induced Activation of Transforming Growth Factor-ß1 in Pulmonary Fibrosis. American Journal of Respiratory and Critical Care Medicine 2016; 194: 84-96.

[6] Xu Y, Mizuno T, Sridharan A, Du Y, Guo M, Tang J, Wikenheiser-Brokamp KA, Perl AKT, Funari VA, Gokey JJ, Stripp BR, Whitsett JA. Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. JCI Insight 2016; 1: e90558-e90558.

[7] Roach KM, Sutcliffe A, Matthews L, Elliott G, Newby C, Amrani Y, Bradding P. A model of human lung fibrogenesis for the assessment of anti-fibrotic strategies in idiopathic pulmonary fibrosis. Sci Rep 2018; 8: 342.

[8] Borok Z, Horie M, Flodby P, Wang H, Liu Y, Ganesh S, Firth AL, Minoo P, Li C, Beers MF, Lee AS, Zhou B. Grp78 Loss in Epithelial Progenitors Reveals an Age-linked Role for Endoplasmic Reticulum Stress in Pulmonary Fibrosis. 2020; 201: 198-211.

[9]  Hill C, Li J, Liu D, Conforti F, Brereton CJ, Yao L, Zhou Y, Alzetani A, Chee SJ, Marshall BG, Fletcher SV, Hancock D, Ottensmeier CH, Steele AJ, Downward J, Richeldi L, Lu X, Davies DE, Jones MG, Wang Y. Autophagy inhibition-mediated epithelialmesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis. Cell Death Dis 2019; 10: 591-591.

Developing healthy practices could help you live a longer life.

Starting Your Personal Longevity Strategy

Every day, researchers get together in their labs and try to find ways of bringing aging under medical control. Despite the ongoing global effort, it is estimated that a relatively complete system of controlling biological aging is at least 20 years away.

That means there is likely going to be considerable time before life extension technologies are available. In order to live long enough to benefit from them, developing a personal longevity strategy is a wise idea.

The goal therefore, would be to live at least another 20 years in relatively good health. The difficulty of this depends on how old you are now, but regardless of your age, you can develop a personal longevity strategy today. To help you on this path, we have created some practical health tips to help you take care of yourself and your family.

Know yourself

The first and most important step towards developing a personal longevity strategy is proper diagnostics.

Many diseases and conditions start silently. It’s possible to feel changes in the body without being able to attribute them to deficiencies or abnormal biomarkers. When we get sick, we simply feel bad or in pain. It is important to find out what is wrong – preferably, before it becomes a real problem.

To receive valuable data on your health, you can use three types of diagnostic tests. All of them are valuable, but some of them might be more appropriate than others in different cases.

  • Genetic tests spot any genetic predisposition to a disease. Many companies now offer all sorts of genetic tests, from individual diseases to a full exome (the coding part of the genome) test or a full DNA test. In most cases, you only need to take such a broad test once in order to use its information to improve decision making and help your medical advisor understand your condition.
  • Regular complex check-ups to see what is going on in your body. Complex checkups test a large number of biomarkers, such as lipid profile, thyroid hormones, glucose and insulin, biomarkers of the liver and kidney, inflammation biomarkers such as C-reactive protein and interleukin-6, and levels of certain vitamins and minerals that are vital for health and well-being. Biomarker composition normally changes with age, and older people may benefit from checking more things than younger people.
  • Regular check-ups specific to your diseases or conditions that will show you how well treatments are working. If you are taking drugs for age-related diseases regularly check if each drug is working well and does not need replacement or dose adjustment. This way, you make sure that each treatment is beneficial and keeping your diseases under control.

Talk to your medical advisor

Most people don’t have a medical degree. While you can find lots of useful information on the internet, a visit to a doctor remains the most reliable way to get a proper assessment of your physical condition.

Properly interpreting data is vital for developing a good strategy, and a doctor may advise you on how to combine your treatments in a safe way if you need to address several issues at once. Some drugs may be incompatible, or your genetic layout may predispose you to a weak response to certain treatments. A doctor can also prescribe additional tests if the picture is unclear and there is no reliable diagnostic hypothesis.

Working together with medical advisors, we can achieve the best results possible. Here are some tips that may make your visit more effective:

  • Describe your sensations in enough detail.
  • Try to remember what happened before or after you felt that something was wrong, including social situations, sports, or overwork that may have served as stress factors
  • List the medications that you are already taking and the reasons why you are taking them; this helps to exclude the influence of those medications on the diagnosis.
  • Ask about the suspected diagnosis and how to confirm it.
  • Ask about what can be done in your case, including the best strategy and the second-best strategy.
  • Don’t forget to set another appointment to check how your treatment is going.

New supplements should be introduced one at a time

The range of dietary supplements is already overwhelmingly large and it is important to develop a science-based approach when considering taking them. Before taking anything, carefully check the information about each supplement and see if it can indeed be beneficial.

There is a lot of misleading marketing and overpriced supplements with little to no supporting data that they will do anything for longevity, so due diligence is a must before considering taking anything. Some supplements contain vitamins that might already be abundant in the body, some can interact with medical treatments in the wrong way, and some may be incompatible with you personally.

In any case, if you choose to take supplements, it makes sense to introduce only one supplement at a time into your regime and carefully check how you feel after it. If you use several new supplements or drugs at once and feel bad, you may never understand what exactly has happened nor which substance is causing issues.

Supplements should supplement a healthy lifestyle, not replace it

It is very tempting to stop working on maintaining a healthy lifestyle if you can just take a drug or a supplement that may prolong healthy life. However, the increase in healthy years that often come from a good diet and physical activity can easily compete with the effects of existing therapies that slow down age-related diseases.

This is largely explained by deeply ingrained genetic mechanisms that make mild hunger, physical activity, good sleep, and a diet with a low glycemic index beneficial for health. For thousands of years, humans have adjusted to harsh living conditions, such as hard work and long walks just to gather food, until the body learned how to use those survival efforts to postpone age-related diseases, reduce their risks, and stay healthy for longer. This legacy is not to be underestimated.

Some simple things you can do now

While we are waiting for powerful longevity treatments to arrive, here are some tips.

  • Try to find out how many calories your body needs to be healthy and eat as close to this as is practical. A calorie counter app may help you to track your intake.
  • Limit the amount of fast carbs in your diet. WHO recommends only 5% of your calorie intake be from free sugars, such as cakes and sweet drinks.
  • Eat plenty of raw vegetables and fruits. According to WHO, over 400 grams of vegetables every day should provide health benefits. And fiber is good for beneficial gut bacteria.
  • Try to walk more than 10000 steps a day. If you have health issues, adjust this number to your actual ability, but still move as much as you can
  • If you are a healthy adult, do some intense physical activity 2-3 times a week. If you have some health issues, adjust this amount of exercise to your actual ability but still try to make your muscles work.
  • Sleep in a room that is dark, ventilated, and cool enough. 7-8 hours of sleep seems to be a healthy amount of sleep. If your sleep is much shorter, you might need to discuss it with your medical advisor – as you age, the production of the sleep hormone melatonin decreases, and your advisor might recommend taking it as a supplement.
  • Practice some self-regulation techniques – meditation or relaxation can contribute to better sleep and better control over your health behaviors.
  • Saunas have a number of health benefits that relate to health and longevity, try to use them as often as possible. The mild heat stress causes your cells to produce protective proteins and increase the activity of cellular repair systems.
  • Get rid of bad habits such as heavy drinking, smoking, and harmful drugs. These may reduce your healthy period of life because they accelerate aging.

Get some good company

It has been shown in numerous studies that social interaction can be beneficial for your health. Even though the pandemic currently requires many of us to limit in-person meetings and wear protective masks, having friends and communicating with relatives on a regular basis is important.

Apart from the enjoyment from human companionship, your relatives or friends may notice if something is going wrong and help you in case of a crisis. Helping other people may also have positive effects on your health.

People who volunteer often feel happier and more fulfilled in life than those who don’t. Centenarians are known to contribute to their social circles, which might be a factor why they live so long.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

PEARL Rapamycin Campaign

PEARL Is Funded, Rapamycin Longevity Clinical Trials Begin

Today is a doubly important day: it marks the final day of the PEARL campaign and it is a celebration of another victory for the life extension community.

PEARL smashed its initial fundraising goal and sailed through its two stretch goals, raising just under $183k thanks to the generous support of the community.

What is PEARL?

The Participatory Evaluation (of) Aging (with) Rapamycin (for) Longevity Study, or PEARL, will launch the first large-scale placebo-controlled clinical trial to determine the effects of rapamycin on human aging. The principal investigator is Dr. James P. Watson based at UCLA.

What is rapamycin?

Rapamycin is a naturally occurring antifungal antibiotic produced by soil bacteria originally discovered on Easter Island, also known as Rapa Nui.

While most people know it as a drug used in high doses for organ rejection during transplants, it has potential as a drug to slow down aging in far lower doses. It was the first drug proven to extend the lifespan of mice, even when given late in life, and has been shown to reliably increase the lifespan of yeast, worms, and rats.

Rapamycin works through the mTOR signaling pathway, a master regulator of cellular and energy metabolism, and a potent trigger of autophagy, the ultimate cellular recycling mechanism.

Recent research shows that it also improves how our DNA is stored which helps combat genomic instability resulting from DNA damage and harmful epigenetic alterations to gene expression which drive the aging process.

Until now, there has not been a proper clinical trial to evaluate if rapamycin can slow down aging in humans. PEARL is going to change that thanks to our supporters.

Why PEARL is an important milestone for life extension

This large-scale clinical trial will allow the researchers to find out if the effects of rapamycin will translate to people. If that were to happen, then the potential impact could be massive. Having a drug that demonstrably slows down human aging confirmed by large-scale clinical trial data would really open doors. The data could help garner wider public support for life extension therapies as well as support dialogue with policymakers and healthcare regulatory bodies.

Also, rapamycin is a relatively cheap, off-patent, generic drug and widely available. It has been a registered drug for decades with a well-known safety profile and characteristics. If longevity benefits are confirmed, then it could potentially start being used in healthcare to address aging almost immediately.

The community should be proud of what it has achieved today

This has been the most successful crowdfunding campaign we have ever hosted on lifespan.io, and it is all thanks to you, our amazing life extension community.

Thank you to everyone who has supported PEARL!

Over 409 of you have donated just under $183k to the campaign since its launch on May 17th, helping to make this one of the largest, if not the largest, crowdfunded aging focused biology projects in the world.

This successful fundraising really showcases the growing power of the life extension community, and part of this power comes from the cryptocurrency community. In the last few years, thanks to people like Vitalik Buterin, there has been an increasing level of support from the cryptocurrency community, which is greatly appreciated.

Special thanks

The PEARL team and lifespan.io are incredibly grateful to everyone who donated to PEARL and would like to give special thanks to Vitalik Buterin, Tom Moya Schau, Micah Zoltu, and Brad Armstrong, who contributed to the campaign with large donations. Thank you so much for your wonderful support; you have really helped to drive this project to success!

What is next?

Due to the huge success of the crowdfunding campaign, the PEARL team wanted to let you all know how the additional funds would be used. The extra money will allow the researchers to measure additional important biomarkers, which will further strengthen the data.

The original planned biomarkers:

  • IGF-1 (fasting)
  • Lipid Panel, Standard
  • TNFa
  • IL-6
  • VLDL
  • Comprehensive Metabolic Panel*
  • HgAC1
  • Uric Acid
  • CBC & DIFF
  • CD4/CD8
  • CMV IgG titers
  • hs-CRP
  • Vitamin D, 25-OH Total  (VIT D,25-OH,TOTAL,IA)
  • sirolimus level

The extra funds will be used to measure these additional biomarkers:

  • Cystatin C
  • GDF 15
  • Adiponectin
  • Leptin

Once again from the PEARL team and lifespan.io, thank you to everyone who has helped make this project possible! For people in the U.S. interested in participating, please get in touch with Agelessrx and a trial administrator should get back to you.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Elderly muscle

The Aged Microenvironment Linked to Sarcopenia

Muscular degradation with age isn’t the result of a decline in the intrinsic regenerative ability of muscles, according to new research [1].  Instead, sarcopenia is likely due to changes in the muscle microenvironment that reduce repair and regeneration.

Declining muscles

Age-related muscle loss can begin as early as a person’s fourth decade, and sarcopenia can eventually lead to a cumulative loss of 30-50% of skeletal muscle mass. The complicated process involves a lot of interacting factors, including the gut microbiome and changes in the muscle microenvironment. Accumulating damage to muscle tissue doubtlessly plays a part, but it’s unclear why this damage doesn’t get repaired.

One suggested possibility has been that the mechanisms responsible for muscle repair might become exhausted with age; therefore, the quiescent muscle precursor cells that normally produce and regenerate muscle lose their ability to do so. However, it’s also possible that there is no change in the intrinsic competence of these cells and that muscle damage goes unrepaired because of changes in the muscle microenvironment.

To determine which of these possibilities is correct, a team of U.S. researchers developed and used a system to graft human muscles into mice. They collected muscle tissue from human cadavers that had undergone autopsies and transplanted it into mice. By using tissue from cadavers of people from different ages, they were able to evaluate the intrinsic regenerative ability of muscle cells at these ages.

Undaunted stem cells

The transplants were equally successful regardless of whether the tissue came from the body of a 36-year old or a 78-year old. Donor tissue from cadavers of various ages integrated into the mouse host and began producing muscle within three weeks and continued for at least six weeks. The researchers also carried out a transcriptomic analysis and detected the expression of human transcription factors involved in muscle differentiation.

These findings make it clear that precursor cells in elderly people retain the ability to generate muscle tissue. They do exactly that when placed in an appropriate environment, such as in healthy mice. The fact that the damage accumulates in elderly muscle tissue thus cannot be attributed to a decrease in the regenerative competence of these cells. The researchers argue that the most likely explanation is that changes in the muscle microenvironment somehow reduce regenerative competence.

The team also tested transplants of tissue after different post-mortem intervals to find out how long the cells retained their regenerative capacity. They found that the transplants were still successful after 11 days, the longest interval they tested. Not only were the transplants successful but there was no change in the success rate from shorter intervals. This suggests that the muscle results are highly resistant to the anoxic conditions of post-mortem tissues.

Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third potential option is that the aged environment becomes inimical to the conduct of muscle regeneration. In the present study, we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle microenvironment such as to disfavor the myogenic function of these cells.

Conclusion

Figuring out how and why sarcopenia happens is obviously important to being able to address it, and this study brings us one step closer to that. The xenografting transplant approach, together with the demonstration that muscle tissue can be harvested from cadavers of different ages at varying times after death, will also likely prove useful tools in our efforts to understand and control sarcopenia.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Novak, JS, et al. Human muscle stem cells are refractory to aging. Aging Cell (2021), doi: 10.1111/acel.13411
Blood cells in an artery

Brain Blood Flow Restriction Resembles Brain Aging in Mice

A mouse study published in Aging Cell has outlined the similarities between artificially restricted cerebral blood flow and the reduced blood flow associated with aging.

Aiming to understand vascular dementia

Prior research has shown that reduced cerebral blood flow, known as hypoperfusion, results in vascular dementia and brain atrophy through multiple mechanisms, including neuroinflammation and mitochondrial dysfunction [1]. The researchers wanted to determine which genes and signaling pathways are involved in the destructive processes of hypoperfusion and how they relate to normal aging. They focused their study on the hippocampus, a critical part of memory, learning, and executive function that is strongly affected by vascular dementia.

Restricting blood flow to match aging

In this experiment, mice were subjected to bilateral common cortical artery stenosis (BCAS), a procedure that uses microcoils to artificially induce hypoperfusion, reducing the blood available to the brain. This procedure reduced the cerebral blood flow of young mice nearly exactly to that of old mice immediately afterwards, taking away roughly 30% of their cerebral blood flow and thus brain oxygen.

After 7 days, the blood flow of young mice had slightly increased, but this procedure resulted in substantial changes to their gene expression, particularly after 30 days. These genes included many critical functions of neurons along with fundamental metabolic processes, as their brains struggled to perform their function in a low-oxygen environment.

Interestingly, while the blood flow of older mice was further reduced by this procedure, they changed their gene expression substantially less than young mice did, and their blood flow returned closer to their norm. It is logical to conclude that, as their blood flow was already being restricted, the procedure caused few effects that had not already occurred.

The mitochondrial connection

Genes relating to fundamental aspects of the ribosome, the cellular machinery that engages in protein synthesis, as well as many genes related to mitochondrial integrity, were still different between young mice subjected to BCAS and normal old mice.

However, the researchers noted that young mice subjected to BCAS and normal old mice had similar gene expressions related to mitochondrial oxidation and, partially, the production of NAD+ from NADH and the basic synthesis of ATP, the energy our cells use to function. The mitochondria, the powerhouses of the cell, were prohibited from producing as much power as they normally would, both in BCAS and aging. Other similarly downregulated genes included heat shock proteins that serve neuroprotective functions.

This begs the question of how much of aging is caused by macro-scale physical processes that are caused by other aspects of aging. These results suggest this sort of causal chain: as some processes of aging cause ischemia, this limits critical oxygen flow to the brain, thus resulting in fewer neuroprotective proteins and increased mitochondrial dysfunction. More research is needed to see if this holds true in other tissues and in human beings.

Abstract

Vascular dementia (VaD) is a progressive cognitive impairment of vascular etiology. VaD is characterized by cerebral hypoperfusion, increased blood-brain barrier permeability and white matter lesions. An increased burden of VaD is expected in rapidly aging populations. The hippocampus is particularly susceptible to hypoperfusion, and the resulting memory impairment may play a crucial role in VaD. Here we have investigated the hippocampal gene expression profile of young and old mice subjected to cerebral hypoperfusion by bilateral common carotid artery stenosis (BCAS). Our data in sham-operated young and aged mice reveal an age-associated decline in cerebral blood flow and differential gene expression. In fact, BCAS and aging caused broadly similar effects. However, BCAS-induced changes in hippocampal gene expression differed between young and aged mice. Specifically, transcriptomic analysis indicated that in comparison to young sham mice, many pathways altered by BCAS in young mice resembled those already present in sham aged mice. Over 30 days, BCAS in aged mice had minimal effect on either cerebral blood flow or hippocampal gene expression. Immunoblot analyses confirmed these findings. Finally, relative to young sham mice the cell type-specific profile of genes in both young BCAS and old sham animals further revealed common cell-specific genes. Our data provide a genetic-based molecular framework for hypoperfusion-induced hippocampal damage and reveal common cellular signaling pathways likely to be important in the pathophysiology of VaD.

Conclusion

While this study builds on our knowledge of the effects of long-term hypoperfusion on gene expression and makes strides in uncovering the mechanisms behind vascular dementia, it also pointedly illustrates just how much damage aging actually causes. To cause a young mouse to suffer the same amount as an old mouse in just one way, researchers must squeeze the arteries going to its brain. The old mouse still has many more medical problems that lead to dysfunction and death; to cause a young mouse to suffer all the problems of an old mouse through surgery would be both inhumane and impossible.

Meanwhile, ischemic stroke, vascular dementia, and many more crippling and fatal age-related diseases are occurring, right now, in hundreds of millions of human beings around the world.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Aliev, G., Obrenovich, M. E., Smith, M. A., & Perry, G. (2003). Hypoperfusion, mitochondria failure, oxidative stress, and Alzheimer disease. Journal of Biomedicine and Biotechnology, 2003(3), 162-163.

Creatine helps to build muscle and may slow down aging.

What is Creatine? A Summary of Methylguanidine Acetic Acid

Meat is rich in creatine, an important energy buffer in muscle cells, and the main constituent of a popular sports supplement used by athletes. However, we’re now finding out that there’s more to it than ‘meats’ the eye.

What is creatine?

Creatine (α-methyl guanidine-acetic acid) is a substance that is present in our muscle cells. Functionally, it helps our muscles to produce energy for lifting weights, high-intensity exercise, and other strenuous activities. It has enjoyed great popularity as a supplement with athletes and bodybuilders in order to gain muscle, boost strength and increase exercise performance.

It was first identified by French chemist Michel Eugène Chevreul in 1832, who isolated it from skeletal muscle. Due to its presence in living tissue, Chevreul named it after the Greek word κρέας (kreas), meaning meat.

In 1912, Otto Folin and Wiley Glover Denis of Harvard University found that ingesting creatine led to a significant increase in intramuscular stores [1], sparking an interest in its potential as an oral supplement.

By the 1930s, German scientists began to study the relationship between creatine levels and muscle contraction, concluding that the more creatine present in muscle cells, the longer they could contract before producing lactic acid [2-3], allowing for extended training times.

During the 1960s, an interest surged in the possible uses of creatine to treat muscle diseases. In 1964, Fitch et al. were able to show that the skeletal muscles of muscular dystrophy patients have lower concentrations than their normal counterparts, which they attributed to a defect in creatine binding in muscle cells [4-5].

The potential of creatine as a performance-enhancing supplement came into public scrutiny after the 1992 Barcelona Olympics, in which several gold medallists admitted to taking it during training. Today, supplements exist in a wide variety of forms and are one of the most widely used nutritional supplements worldwide [6].

What foods contain creatine?

It is produced inside the body from the amino acids glycine and arginine, and it is widely distributed to tissues with high energy demands, such as the brain and muscles. About 95% of the body’s creatine is stored in skeletal muscle, but it is also found in small amounts in the liver, kidneys, and testes.

On average, the body produces approximately 1 gram of creatine per day in young adults [7-8], while the rest is obtained through diet. 

Creatine is naturally occurring in many foods, particularly animal protein, such as meat and fish. One pound of raw beef contains approximately 2.3g of creatine, while one pound of raw salmon contains up to 2g.

Cooking denatures creatine, so unless you like your steak extra bloody or are a big fan of sashimi, it will be difficult to get enough of it in your diet to benefit from its health properties. Red meat is also high in saturated fat and may increase your risk of all-cause mortality [9-10], so consuming that much meat to begin with might not be the wisest choice.

Luckily, it is widely available as a health supplement, and is extremely affordable. This is particularly relevant for vegans and vegetarians, whose intake is greatly diminished or absent altogether. These supplements have been found to have increased potency in vegetarians and confer other beneficial effects, such as increased cognitive capacity and performance, compared to omnivores [11-12]. Recently, some studies have suggested that this might be due to an underlying creatine deficiency [13-14].

Creatine benefits

It is an important molecule in the maintenance of cellular adenosine triphosphate (ATP) homeostasis, the cell’s balancing act. ATP is essential for the upkeep of physiological processes and is the main transporter of energy for use in metabolism. During exercise, ATP levels in muscle cells deplete very quickly, leading to the accumulation of lactic acid and the onset of cramps.

In order to be able to replenish ATP quickly, muscle cells contain stores of phosphocreatine (PCr), a high-energy phosphate compound which can donate a phosphate group to ADP to quickly form ATP. This reaction is reversible, and during periods of low energy demands, ATP can be used to convert creatine back to phosphocreatine for later use [15-16]. This important “energy reservoir” is what allows it to improve exercise performance.

The use of creatine supplements in combination with strength training has been found to increase muscle fiber size [17-18] and improve performance in high-intensity repetitive exercise in several studies [19-21]. Other studies have found no beneficial effects on performance, however [22-25]. This inconsistency has recently been attributed to conflicting experimental designs, making the literature on the effects of creatine in humans difficult to interpret.

Creatine is an energy buffer

Due to its ability to act as an energy buffer, creatine has also been shown to be neuroprotective against low oxygen levels, preventing neuronal death by regulating NMDA receptor function – a critical channel for the development of the central nervous system – and reducing oxidative stress [26-27].

There is evidence that impairments in energy production may play a role in the development of neurodegenerative diseases such as Huntington’s [28-29], and a study exploring the effect of oral administration of creatine on brain lesions found that feeding animals a mixture containing 1% creatine lead to an 83% reduction in lesion volume after two weeks [30]. Other studies have found that it might protect the brain from damage after stroke [31-33], and increase overall cognitive performance in the elderly [34] but not in young adults [35].

Phosphocreatine has also been found to be cardioprotective in several studies, particularly during heart failure, where it becomes the primary source of energy for cardiac tissue [36-37]. During periods of low oxygen, the creatine kinase system plays an important role in cardiac recovery by providing high-energy phosphate to the heart muscles [38].

Last but not least, creatine may restore skin elasticity and reduce wrinkles by replenishing collagen stores [39-40] and protecting against UV-induced DNA damage [41-42]. One study using creatine as a topical skin cream (compounded with glycerol and guarana) found a significant skin-tightening effect and reduction of wrinkles over 6 weeks [43], while another study, which used topical creatine and folic acid, also found notable improvements in skin regeneration and elasticity [44].

Disclaimer

This article is only a very brief summary, is not intended as an exhaustive guide, and is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use or any product or supplement vendor, and all discussion here is for scientific interest.

References

[1] Folin, Otto; Denis, W. (1912). Protein metabolism from the standpoint of blood and tissue analysis. Journal of Biological Chemistry, 12 (1): 141–61.

[2] Lohmann, K. (1934). Ober die enzymatische Aufspaltung der Kreatinphosphore; zugleich ein Beitrag zum Chemismus der Muskelkontratraktion. Biochem. Z. 271, 264.

[3] Lundsgaard, E. (1930). Weitere Untersuchungen iiber Muskelkontraktionen ohne Milchsiiurebildung. Biochem. Z. 227, 5,1.

[4] Fitch, C. D., & Sinton, D. W. (1964). A Study of Creatine Metabolism in Diseases Causing Muscle Wasting. Journal of Clinical Investigation, 43(3): 444–452.

[5] Vignos, P.J.JR & Warner, J.L. (1963). Glycogen, creatine, and high energy phosphate in human muscle disease. Journal of Laboratory and Clinical Medicine 62: 579.

[6] Williams M.H., Kreider R.B., Branch J.D. (1999). Creatine: The Power Supplement. Human Kinetics, Champaign, IL.

[7] Brosnan J.T., da Silva R.P., Brosnan M.E. (2011). The metabolic burden of creatine synthesis. Amino Acids 40 (5): 1325–31.

[8] Cooper R., Naclerio F., Allgrove J., Jimenez A. (2012). Creatine supplementation with specific view to exercise/sports performance: an update. Journal of the International Society of Sports Nutrition 9 (1): 33.

[9] Sinha R., Cross A.J., Graubard B.I., et al. (2009). Meat intake and mortality: a prospective study of over half a million people. Archive of Internal Medicine 169(6):562–71.

[10] Larsson S.C. & Orsini N. (2014). Red meat and processed meat consumption and all-cause mortality: a meta-analysis. American Journal of Epidemiology 179: 282–289.

[11] Lukaszuk J.M., et al. (2005). Effect of a defined lacto-ovo-vegetarian diet and oral creatine monohydrate supplementation on plasma creatine concentration. Journal of Strength and Conditioning Research 19(4):735-40.

[12] Maccormick V.M., et al. (2004). Elevation of creatine in red blood cells in vegetarians and nonvegetarians after creatine supplementation. Canadian Journal of Applied Physiology 29(6):704-13.

[12] Benton D., Donohoe R. (2011). The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. British Journal of Nutrition 105(7):1100-5.

[13] Rae C., et al. (2003). Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proceedings. Biological Sciences 270(1529): 2147-50.

[14] Meyer RA, et al. (1984). A simple analysis of the “phosphocreatine shuttle”. American Journal of Physiology 246:C365–C377

[15] Bessman S.P., Carpenter C.L. (1985). “The creatine-creatine phosphate energy shuttle.” Annual Review of Biochemistry 54:831–862

[16] Volek et al. (2004). The effects of creatine supplementation on muscular performance and body composition responses to short-term resistance training overreaching. European Journal of Applied Physiology 91(5-6):628-37.

[17] Olsen et al. (2006). Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. Journal of Physiology 573(Pt 2): 525-34.

[18] Dawson B., Cutler M., Moody A., Lawerence S., Goodman C., Randall N. (1995). Effects of oral creatine loading on single and repeated maximal short sprints. Australian Journal of Science and Medicine in Sports 27, 56-61

[19] Meir R. (1995) Practical application of oral creatine supplementation in professional rugby league: A case study. Australian Strength and Conditioning Coach 3, 6-10.

[20] Jacobs I., Bleue S., Goodman J. (1997) Creatine ingestion increases anaerobic capacity and maximum accumulated oxygen deficit. Canadian Journal of Applied Physiology 22, 231-243

[21] Barnett C., Hinds M., Jenkins D.G. (1995) Effects of oral creatine loading on multiple sprint cycle performance. Australian Journal of Science and Medicine in Sports 28, 35-39

[22] Snow R.J., McKenna M.J., Selig S.E., Kemp J., Stathis C.G., Zhao S. (1998) Effect of creatine supplementation on sprint exercise performance and muscle metabolism. Journal of Applied Physiology 84, 1667-1673

[23] Deutekom M.J., Beltman G.M., De Ruiter C.J., De Koning J.J., De Haan A. (2000) No acute effects of short-term creatine supplementation on muscle properties and sprint performance. European Journal of Applied Physiology 82, 23-229

[24] Biwer C.J., Jensen R.L., Schmidt W.D., Watts P.B. (2003) The effect of creatine on treadmill running with high-intensity intervals. Journal of Strength and Conditioning Research 17, 439-445

[25] Bird, S. P. (2003). Creatine Supplementation and Exercise Performance: A Brief Review. Journal of Sports Science & Medicine, 2(4), 123–132.

[26] Genius J., et al. (2012). Creatine protects against excitoxicity in an in vitro model of neurodegeneration . PLoS One 7(2).

[27] Matthews R.T., et al. (1999). Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol.

[28] Tabrizi S.J., et al. (2005). High-dose creatine therapy for Huntington disease: a 2-year clinical and MRS study. Neurology 64(9):1655–1656

[29] Matthews et al. (1998). Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. Journal of Neuroscience 18:156–163.

[30] Balestrino et al. (1999). Exogenous creatine delays anoxic depolarization and protects from hypoxic damage: dose-effect relationship. Brain Research, 816, 124–130.

[31] Dechent et al., (1999). Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. American Journal of Physiology 277(3 Pt 2):R698-704.

[32] Balestrino et al. (2002). Role of Creatine and Phosphocreatine in Neuronal Protection From Anoxic and Ischemic Damage. Amino Acids 23 (1-3), 221-229.

[33] McMorris T., et al. (2007). Creatine supplementation and cognitive performance in elderly individuals. Neuropsychology, Development, and Cognition, Section B: Aging Neuropsychology and Cognition 14(5):517-28.

[34] Rawson E.S., et al. (2008). Creatine supplementation does not improve cognitive function in young adults. Physiological Behaviour 95(1-2):130-4

[35] Akki A., et al. (2012). Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium. American Journal of Physiology: Heart and Circulatory Physiology 303(7).

[36] Rodriguez P., et al. (2003). Importance of creatine kinase activity for functional recovery of myocardium after ischemia-reperfusion challenge. Journal of Cardiovascular Pharmacology 41(1):97-104.

[37] Bittl J.A., Balschi J.A., Ingwall J.S. (1987). Contractile failure and high-energy phosphate turnover during hypoxia: 31P-NMR surface coil studies in living rat. Circulation Research 60(6):871-8.

[38] Neubauer S, et al. (1988). Velocity of the creatine kinase reaction decreases in postischemic myocardium: a 31P-NMR magnetization transfer study of the isolated ferret heart. Circulatory Research 63(1):1-15.

[39] Blatt T., et al. (2005). Stimulation of skin’s energy metabolism provides multiple benefits for mature human skin. Biofactors 25(1-4):179-85.

[40] El-Domyati M., et al. (2002). Intrinsic aging vs. photoaging: a comparative histopathological, immunohistochemical, and ultrastructural study of skin. Experimental Dermatology 11(5):398-405.

[41] Scharffetter-Kochanek K., et al. (1997). UV-induced reactive oxygen species in photocarcinogenesis and photoaging. Biological Chemistry 378(11):1247-57.

[42] Lenz H., et al. (2005). The creatine kinase system in human skin: protective effects of creatine against oxidative and UV damage in vitro and in vivo. Journal of Investigative Dermatology 124(2):443-52.

[43] Peirano R.I., et al. (2011). Dermal penetration of creatine from a face-care formulation containing creatine, guarana and glycerol is linked to effective antiwrinkle and antisagging efficacy in male subjects. Journal of Cosmetic Dermatology 10(4):273-81

[44] Knott A., et al. (2008). A novel treatment option for photoaged skin. Journal of Cosmetic Dermatology 7(1):15-22

Magnifying glass on cancer

First Multi-Cancer Blood Test Available Now

Biotech company GRAIL made history earlier this month when it introduced the first commercially available multi-cancer blood test. The test is based on analyzing tumor DNA in circulation and could be a game-changer in the field of cancer diagnostics, especially if the company continues to improve it.

Discovering cancer early

Medicine has made great strides in fighting cancer, but it remains one of the most lethal diseases in the world. Even when therapy is successful, cancer can have a devastating effect on the patient’s quality of life and remaining lifespan. While many novel therapeutical approaches are being explored, including immunotherapy, the next major success could lie in better diagnostics.

Cancer is much more treatable at early stages (the average 5-year survival rate is 91% for early-stage cancer and only 26% for late-stage cancer) [1] but also much harder to detect. Only a handful of cancers have an approved early detection method, which can be invasive or uncomfortable, such as colonoscopy. This makes people apprehensive about taking the test and results in fewer early detections. One of the rare exceptions is prostate cancer, which can be detected by the PSA (prostate-specific antigen) blood marker, but this does not change the overall picture: most cancer types currently lack a recommended early screening option, invasive or otherwise.

A multi-cancer blood test addresses two major problems. First, it is no more invasive than a regular blood test, so people have fewer reasons to avoid it. Second, a single test can detect dozens of types of cancer, rather than one specific type.

It’s in the blood

GRAIL’s test, Galleri, is based on analyzing the methylation patterns of circulating cell-free DNA (cfDNA), which consists of degraded DNA molecules. These remnants, which have escaped from living or dead cells into the bloodstream, have a length of 50 to 200 base pairs. Cancer cells also shed cfDNA, which can be recognized by specific methylation patterns using machine learning. Yet, even with cutting-edge technologies, it is not easy to locate trace amounts of cfDNA from cancer cells among other free-floating DNA, which makes GRAIL’s achievement even more impressive.

In trials, Galleri’s sensitivity was highly dependent on the clinical stage of the disease, which is to be expected [2]. Across all cancer types, sensitivity (the probability that a test will correctly indicate that someone has the disease) was 18% at stage I, 43% at stage II, 81% at stage III, and 93% at stage IV. In many cancer types, including highly prevalent cancers and cancers that lack early detection methods, sensitivity was higher.

Given the lack of alternatives, GRAIL’s test is highly valuable and will undoubtedly save many lives. Galleri also excels in predicting the tissue of origin (TOO) of the cancer signal: in trials, the TOO was correctly predicted in 96% of samples. Overall, Galleri can detect more than 50 types of cancer, a majority of which lack recommended screening tests in the U.S., with a false positive rate of less than 1%.

Support, not replacement

GRAIL admits that Galleri “should complement, not replace, existing single-cancer screening tests”. In a recent paper, GRAIL researchers note that of the 89% cases of prostate cancer that had been diagnosed through a conventional screening by PSA, only 6% were detected by Galleri [3]. For this specific cancer type, Galleri will probably find limited use, but it can do a lot of good in others.

This study also shows that Galleri preferentially detects more aggressive cancers, even when controlled for the stage of the disease. For instance, the test excels at detecting small-cell lung cancer and hormone-receptor negative breast cancer, which are both considered especially deadly. That means that false negatives, the cancer cases that the Galleri test misses, are probably less deadly than the cancers it detects.

In today’s medicine, it rarely happens that a certain field of study is dominated by just one team. Researchers race against each other and build on each other’s advancements. Multi-cancer blood tests are not an exception, with several teams currently working on perfecting the technology [4]. Nevertheless, beating others to the shelves is a major achievement, considering how hard this last leg of the journey is.

Conclusion

A multi-cancer blood test is another sharp arrow in the quiver of oncology. Although it is easier to obtain regulatory approval for a test than for a treatment, a product hitting the market is still a rare event. Improvements in early diagnostics can have a drastic effect on cancer outcomes, especially for cancers that currently lack alternative methods of early detection. It is important to remember that Galleri is the first generation of multi-cancer blood tests, and it will inevitably be improved upon.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Siegel, R. L., Miller, K. D., & Jemal, A. (2016). Cancer statistics, 2016. CA: a cancer journal for clinicians, 66(1), 7-30.

[2] Liu, M. C., Oxnard, G. R., Klein, E. A., Swanton, C., Seiden, M. V., Liu, M. C., … & Youngren, J. (2020). Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Annals of Oncology, 31(6), 745-759.

[3] Chen, X., Dong, Z., Hubbell, E., Kurtzman, K. N., Oxnard, G. R., Venn, O., … & Liu, M. C. (2021). Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA. Clinical Cancer Research.

[4] Chen, X., Gole, J., Gore, A., He, Q., Lu, M., Min, J., … & Jin, L. (2020). Non-invasive early detection of cancer four years before conventional diagnosis using a blood test. Nature communications, 11(1), 1-10.

Strawberries are a source of fisetin.

What is Fisetin? A Summary of Fisetin

We take a look at the popular supplement fisetin and see how it stacks up as a potential anti-aging supplement.

What is Fisetin?

Fisetin is a plant polyphenol and part of the flavonoid group in the flavonol sub-category.  It is present in many trees and plants, including Eudicotyledons, Acacia greggii, Quebracho colorado, Rhus cotinus, and Butea frondosa. In fact, the earliest record of isolated fisetin dates back to 1833 taken from the smoke bush (Rhus cotinus), so it has been around for a long time.

Its basic chemical characteristics were later defined by J. Schmidt in 1886, but it was not until the 1890s when S. Kostanecki defined its chemical structure and confirmed it via synthesis. Kostanecki launched a study of plant pigments during this period and coined group names for sub-categories, including flavones, flavonol, chromones, and chalcones.

The traditional yellow/ochre dye known as young fustic uses fisetin extracted from the wood of the smoke bush and was a popular way to color fabrics and clothes until synthetic dyes replaced it.

What foods contain Fisetin?

It can be found in many common fruits and vegetables, although the amounts can vary considerably.

Fruit/Vegetable Amount in µg/g
Strawberry 160
Apple 26.9
Persimmon 10.6
Lotus Root 5.8
Onion 4.8
Grape 3.9
Kiwi 2.0
Peach 0.6
Cucumber 0.1

Clearly, strawberries have a much higher concentration of this flavonol than other fruits and vegetables, which may be why people associate it with this fruit in particular. Typical supplement pills are in the 100-mg range, which is significantly higher than dietary sources would typically provide. However, without proper clinical trials, there is no way to know if this 100-mg dose is beneficial or harmful in humans.

Of course, the supplement industry offers a fisetin supplement for those wishing to increase their intake beyond that achieved from food.

What is Fisetin good for?

Like many plant polyphenols, it is known to have antioxidant properties and demonstrates the specific biological activity of protecting functional macromolecules against stress, resulting in a benefit to cellular cytoprotection.

It is also known to have anti-inflammatory, chemopreventive, and chemotherapeutic properties.

Fisetin and its senolytic potential

It has been in the spotlight most recently for its potential as a senolytic therapeutic, which can destroy harmful senescent cells that linger in the body and cause inflammation. Senescent cell accumulation is thought to be a reason we age, so fisetin may, in a very real sense, be targeting aging directly and has potential as an anti-aging therapeutic.

This interest in its senolytic properties was initiated in 2018, when researchers from the University of Minnesota Medical School and Mayo Clinic published “Fisetin is a senotherapeutic that extends health and lifespan” in the journal EBioMedicine [1]. The study showed that fisetin given to aged mice could destroy senescent cells and improved both their healthspan and lifespan. Importantly, no adverse side effects were noted, even when the mice were given very high doses.

The researchers also compared it against other compounds, including resveratrol, luteolin, rutin, epigallocatechin gallate, curcumin, pirfenidone, myricetin, apigenin, and catechin. This study showed that it was the most effective of these compounds.

Since fisetin has a good safety profile, Mayo Clinic followed these mouse studies by launching three trials to see if the compound is effective for humans.

Start End Participants
November 15, 2018 April 28, 2020 Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults
February 6, 2018 June 30, 2020 Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Women
January 2, 2018 April 2022 Inflammation and Stem Cells in Diabetic and Chronic Kidney Disease

Further fisetin studies

Fisetin has been studied prior to the interest in senolytics and, like many polyphenols, it has anti-inflammatory activity. While not all of the following studies are directly about aging per se, they do explore inflammation, which is a critical component of aging.

A 2018 study tested fisetin, curcumin, and three modified variants of these two compounds and discovered that they all reduced some biomarkers of aging, increased median lifespan in mice and flies, and reduced the signs of dementia [2]. While the modified compounds worked somewhat better, the unmodified fisetin also worked.

It also appears to have a potent effect on inflammation by blocking the activity of lipoxygenases, thus reducing the level of pro-inflammatory factors [3-4].

There also appears to be some potential for fisetin to address high blood sugar in diabetics. In a 2014 study, researchers discovered that it was able to block the inflammatory response to prevent damage to blood vessels and tissue in mice [5]. Similar results were found for human cell lines tested during the same study.

A 2014 study found that it was an effective treatment for eczema in mice, as it was able to reduce the presence of immune cells such as T cells, mast cells, and eosinophils, which are commonly encountered in the skin lesions that eczema causes [6].

There are a number of additional studies are interest:

Condition PMID
Diabetes PMID: 21738623
Diabetes PMID: 24939606
Diabetes PMID: 23791753
Diabetes PMID: 21816145
Diabetes PMID: 25064342
Hypertension PMID: 26741654
Hypertension PMID: 26759702
Obesity PMID: 23517912

Fisetin side effects

No adverse effects in humans has been reported. However, clinical trial data is still quite limited in particular regarding long-term use. As always, if you do decide to take a fisetin supplement and experience any adverse effects, you should cease taking it immediately and consult your doctor.

Does fisetin work?

Currently, the lack of clinical trial data makes it impossible to say if fisetin is a geroprotector in humans, though the signs are positive for animal studies. With Mayo Clinic and other groups conducting human trials, we likely will not have to wait too long before we have the answers.

It has an good safety profile and is well tolerated and cheap, so if human trials confirm its effectiveness as a geroprotector, it would be a real low-hanging fruit for people with an interest in combating the effects of aging. We will have to wait and see what such trials say before we jump on the bandwagon.

Disclaimer

This article is only a very brief summary. It is not intended as an exhaustive guide and is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use or any product or supplement vendor, and all discussion here is for scientific interest.

Literature

[1] Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., … & McGuckian, C. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28.

[2] Schubert, D., Currais, A., Goldberg, J., Finley, K., Petrascheck, M., & Maher, P. (2018). Geroneuroprotectors: Effective Geroprotectors for the Brain. Trends in pharmacological sciences, 39(12), 1004-1007.

[3] Sadik, C. D., Sies, H., & Schewe, T. (2003). Inhibition of 15-lipoxygenases by flavonoids: structure–activity relations and mode of action. Biochemical pharmacology, 65(5), 773-781.

[4] Maher, P. (2015). Fisetin Acts on Multiple Pathways to Reduce the Impact of Age and Disease on CNS Function. Frontiers in bioscience (Scholar edition), 7, 58.

[5] Kwak, S., Ku, S. K., & Bae, J. S. (2014). Fisetin inhibits high-glucose-induced vascular inflammation in vitro and in vivo. Inflammation Research, 63(9), 779-787.

[6] Kim, G. D., Lee, S. E., Park, Y. S., Shin, D. H., Park, G. G., & Park, C. S. (2014). Immunosuppressive effects of fisetin against dinitrofluorobenzene-induced atopic dermatitis-like symptoms in NC/Nga mice. Food and Chemical Toxicology, 66, 341-349.

Bosu exercise

Exercise Decreases Circulating Senescence Proteins

A new study published in Aging Cell shows that a 12-week program of structured exercise lowers the activity of the inflammatory SASP in people in their mid-60s.

The expected results

To begin the study, participants were measured, weighed, tested on physical abilities, and asked about their quality of life. They then spent a week wearing accelerometers before engaging in a 12-week program of both strength and endurance training, after which they were measured once more and retained their accelerometers for another week.

To little surprise, this exercise program improved the health of the people who partook in it. Participants enjoyed a roughly 1-kilogram loss in fat mass and an almost 2-centimeter decrease in waist circumference, and both physical and mental composite scores increased slightly. Lean mass was also shown to increase very slightly, although this result was not statistically signfiicant.

Interestingly, the baseline activity of the participants did not change after these 12 weeks. People who were sedentary before the intervention remained sedentary afterwards, as measured by their accelerometers.

The decrease of the SASP

Multiple biomarkers associated with the SASP were shown to decrease after this intervention. CD3(+) T cells expressed less of multiple senescence-related genes, including the well-known p16, p21, and TNF-alpha. Ten different proteins related to cellular senescence were also shown to decrease. While the effect was modest, it was statistically significant and broad in scope.

Responders and non-responders

Unfortunately, this intervention did not work on everyone, and the timed up-and-go (TUG) test, which measures how quickly someone can get up, walk, and sit back down again, was used to differentiate people who responded from people who did not. Several SASP biomarkers, some more than others, were correlated with the TUG results. People who were shown to have physically benefited from this intervention were also shown to have reduced their circulating SASP; people who were generally unaffected also had their SASP generally unaffected.

While it is inconclusive as to cause and effect, this result strongly links the decrease of the SASP with the benefits of exercise in older people.

Abstract

Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging-related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence-related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined. Here, we report that a 12-week structured exercise program drives significant improvements in several performance-based and self-reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16, p21, cGAS, and TNFa, were significantly lowered in CD3+ T cells in response to the intervention, as were the circulating concentrations of multiple senescence-related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence-related proteins at baseline were predictive of changes in physical function in response to the exercise intervention. Our study provides first-in-human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise.

Conclusion

While this study went in-depth in its analyses, it only had 34 participants and did not have a control group. For an exercise study, the lack of a control group is less important than in many other studies, as it is impossible to engage in vigorous placebo exercise. While it is possible that the self-reported results were brought about by the placebo effect, this cannot meaningfully explain the weight loss, physical improvements, and SASP decrease experienced by the people who benefited from this regimen.

The SASP and other biomarkers of aging do not significantly, spontaneously decrease in aged individuals. Therefore, people looking to achieve longevity should seek safe and proven interventions that decrease these biomarkers, reduce the effects of biological aging, and improve their health.

In this case, the intervention is something that is very inexpensive and available to nearly everyone. While few people can afford personal trainers and many seniors have their exercise options limited due to other effects of aging (such as osteoporosis), regular exercise has repeatedly been shown to improve human health, even in the elderly. This study simply sheds light on some of the reasons why this happens and a potential biomarker-based method for determining whether or not any given exercise program is working as intended.

The researchers state the most crucial fact as follows:

Exercise remains the most promising intervention to improve physical function in older adults.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Chromatin and histones

Rapamycin Improves How Our DNA Is Stored

Researchers have demonstrated that rapamycin, a drug that has long been believed to slow down aging, changes the way DNA is stored inside cells to support gut health and longevity [1]. This improvement to DNA storage has been observed in both fruit flies and mice in the lab, and the researchers believe that those benefits could translate to humans.

Our DNA is stored inside our cells and is so tightly and efficiently packed that each two-meter-long molecule fits into the tiny cell nucleus. Our cells achieve this by winding the DNA a number of times around the histones, a family of proteins associated with nuclear DNA that helps to compact it into chromatin. Once the DNA is compacted and wrapped, it can then start forming chromosomes.

How tightly wound the DNA is around the histones also decides which genes can be expressed. Interestingly, the number of histones is also known to decline with advancing age in various species. This would, by its nature, lead to less tightly packed DNA and, presumably, more genes being expressed, which is not good news if some of those genes support aging.

Until now it was not clear if these changes in histone numbers might be a point of intervention in slowing aging.

A new target of rapamycin 

Rapamycin is best known for its targeting of the TOR pathway, so much so that TOR stands for target of rapamycin. This suppression of TOR is why researchers have long believed it could potentially slow down aging.

TOR is one of the four key metabolic pathways that regulate aging. Studies have shown that turning down the activity of this pathway reliably increases lifespan in yeast, worms, and mice. Rapamycin reduces the activity of TOR, which regulates energy metabolism and nutrient sensing.

It also influences an array of cellular functions, including stress status and protein assembly. Finally, it has been shown to be a potent inducer of autophagy in a wide range of cells, including yeast and mammalian cells. Autophagy is an important recycling system in cells that allows them to break down defective or unwanted proteins and cellular components in order to assemble new ones.

Essentially, TOR is a master regulator of cellular and energy metabolism, and drugs that can reduce its activity may help to slow down human aging.

The link between TOR and histones

Researchers already knew that histone levels decline with age and influence aging. However, it was unclear whether there was a link between the TOR pathway and those histone levels along with whether such a link could be used as a drug target to potentially slow down aging.

To determine this, the researchers administered rapamycin to fruit flies and examined the organs and tissues both before and after. They observed that histone levels increased following rapamycin treatment. However, perhaps the most intriguing thing was that this only happened in gut cells of the flies and not in other tissues.

Next, the team showed that an increased level of histones in gut cells known as enterocytes could reduce the incidence of tumors and their growth. This also improved gut health and led to an increase in lifespan of the animals. The lifespan was not really a surprise given that rapamycin can reliably increase healthy lifespan in many species.

They also repeated this in mice, and similar results were observed following administration of rapamycin.

Abstract

Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in Drosophila alters chromatin organisation, induces intestinal autophagy through transcriptional regulation, and prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and Wdfy3 transcription, and alters chromatin organisation in the small intestine, suggesting that the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.

Conclusion

This study shows for the first time that there is a direct link between the TOR pathway and histone levels. Further, it also shows that this link is a regulator of longevity and health. The link establishes not only the metabolic targets of rapamycin but also that it has an influence on genomic instability and epigenetic alterations, both of which are primary causes of aging.

These results’ replication in mice also suggests the potential that this could translate to humans and that this is a common mechanism. This finding builds upon our knowledge of why we age and how each of these processes interact to determine longevity.

Rapamycin has the potential to slow down human aging and should be a focus of translational research right now. The initial patent on rapamycin expired in 1992, so it is a generic drug and could be manufactured cheaply and at scale, making it a great candidate for the first potential anti-aging drug.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Lu, Y. X., Regan, J. C., Eßer, J., Drews, L. F., Weinseis, T., Stinn, J., … & Partridge, L. (2021). A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing. Elife, 10, e62233.

computational biology

Calico Scientists Develop Safer Cellular Reprogramming

In a preprint paper, scientists from Calico, Google’s longevity research behemoth, suggest that contrary to our previous understanding, transient reprogramming of cells using Yamanaka factors involves suppressing cellular identity, which may open the door to carcinogenic mutations. They also propose a milder reprogramming method inspired by limb regeneration in amphibians [1].

Rejuvenation that can give you cancer

In 2006, a group of scientists led by Shinya Yamanaka developed a technique for reprogramming somatic cells back into pluripotent stem cells by transfusing them with a cocktail of transcription factors [2]. These four pluripotency-associated genes, Oct4, Sox2, Klf4, and c-Myc (OSKM), became known as the Yamanaka factors. This breakthrough made it possible to produce patient-specific stem cells from their own somatic cells.

On the other hand, induced pluripotent stem cells (iPSCs), which are the product of cellular reprogramming, are known to acquire carcinogenic mutations. This hurdle has been limiting their use, with scientists all over the world trying to overcome it in order to fully utilize iPSCs’ immense potential [3].

When somatic cells revert to the pluripotent state, they also shed many features of cellular aging, effectively becoming young again. iPSCs from young and aged donors are almost indistinguishable, and this similarity remains even after the cells differentiate again into various cell types.

This led scientists to attempt cellular rejuvenation with Yamanaka factors but without reprogramming the cells back to a pluripotent state. Such “transient reprogramming”, in which the factors are introduced for a short period of time, stops before the cells reach the Point of No Return (PNR) on the road back to pluripotency – or so it was thought. Transient reprogramming has been shown to improve multiple physiological functions in aged animals and extend lifespan in progeroid mice [4].

To pluripotency and back

This new paper was published by scientists from Calico, a secretive and well-funded Alphabet (Google) subsidiary in the field of longevity research. Since its inception several years ago, expectations from Calico have been high, but we have only seen a slow trickle of papers. This study is one of the most important to ever come out of the company.

Utilizing their almost unlimited resources, Calico researchers were able to study the effects of transient reprogramming by performing single-cell RNA sequencing for tens of thousands of individual cells. They found that transient reprogramming restored youthful gene expression in adipogenic cells and mesenchymal stem cells, but, at the same time, temporarily suppressed their cell identity programs. These results stand in contrast with the previous notion that transient reprogramming rejuvenates cells without making them revert to a pluripotent state. By analyzing transcription levels of several pluripotency-associated genes on a single-cell level, the researchers showed that such reversion does occur, even if briefly and/or partially, with the cells subsequently reacquiring their cellular identities. These subtle back-and-forth transitions might not have been picked up by previous studies that used less precise bulk analysis.

If cellular identity is indeed suppressed by transient reprogramming, this brings back the specter of oncogenic mutations. The whole idea of transient reprogramming is to rejuvenate cells in vivo, where such mutations cannot be controlled or weeded out.

Can we do with fewer factors?

Since some Yamanaka factors are known to be more oncogenic than others, the researchers analyzed the effects of various combinations of factors to determine whether any of them could be left out. Surprisingly, they found that none of the factors were indispensable – probably because of the way they interact with each other. Apparently, when a combination of factors is introduced to the cell, it activates endogenic transcription of the missing factors. As a result, leaving out any single factor, or even two, only weakens the reprogramming effect, sometimes moderately. As an example, the SO cocktail (half of OSKM), while still effective in transient reprogramming and rejuvenation, was found to suppress cellular identity considerably less than the full array of Yamanaka factors.

The researchers applied the factors both to young and aged cells. While the aged cells were significantly rejuvenated by the treatment, on the transcriptomic map created by the researchers, these aged cells clustered differently from the young reprogrammed cells. This remaining difference probably means that certain features of aging might not be affected by transient reprogramming, but additional research is needed.

Among the gene sets that showed the biggest amplitude of change following the reprogramming was the set that regulates cellular inflammatory response. The genes in this set were upregulated in aged cells and significantly downregulated by reprogramming. As aging is linked to excessive inflammation, a situation known as inflammaging, the ability of transient reprogramming to downregulate these genes is great news.

The amphibian connection

Finally, the researchers attempted an unorthodox approach to transient reprogramming using factors that are associated with multipotency. As opposed to pluripotent cells which can differentiate to almost any cell type, multipotent cells can only differentiate into a small subset of types.

The researchers treated aged murine myocytes (smooth muscle cells) with the multipotency factor Msx1, which also facilitates limb regeneration in some amphibians. This multipotency cellular reprogramming successfully restored youthful gene expression in aged myogenic cells. People probably will not be growing back limbs any time soon, but induced rejuvenation of muscle cells is an important result.

Conclusion

While holding great promise, transient reprogramming apparently is not risk-free. This important paper showcases what can be done with proper funding – such as tens of thousands of single-cell RNA profiles. It expands our understanding of the intricate processes of acquiring and losing cellular identity and of possible ways of using reprogramming techniques to develop therapies.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Roux, A., Zhang, C., Paw, J., Zavala-Solorio, J., Vijay, T., Kolumam, G., … & Kimmel, J. C. (2021). Partial reprogramming restores youthful gene expression through transient suppression of cell identity. bioRxiv.

[2] Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. cell, 126(4), 663-676.

[3] Abad, M., Mosteiro, L., Pantoja, C., Cañamero, M., Rayon, T., Ors, I., … & Serrano, M. (2013). Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature, 502(7471), 340-345.

[4] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.

Chamomile is a great source of Apigenin.

What is Apigenin? A Summary of Apigenin

This active ingredient in chamomile tea has traditionally been used to ease anxiety and reduce stress. We investigate if the scientific studies support this traditional use and how it relates to aging.

What is apigenin?

Apigenin is a very common and widely distributed flavonoid in the plant kingdom. Flavonoids are a class of naturally occurring phytochemicals that are found in plant tissues. Plants use flavonoids to protect themselves from pathogens and radiation from the sun. Some of them even serve a role in attracting pollinating insects, such as bees, butterflies, and moths. Flavonoids are also used by plants to regulate their metabolism.

It is the aglycone of several naturally occurring glycosides, molecules that are connected to sugar molecules. It has been used in folk medicines for centuries as a way to treat anxiety and inflammation. Structurally, it is a solid crystalline with a yellow color, and it has been historically used to dye wool.

How much apigenin in chamomile tea?

Apigenin can be found in chamomile, which is normally drunk as a tea. It is obtained from the dried flowers of Matricaria chamomilla, an annual herb native to Western Asia and Europe. The plant has also been naturalized and grows wild in Australia and the United States.

The amount of apigenin in chamomile teas varies, with some containing significantly more chamomile than others. Teas prepared from chamomile generally have between 0.8% to 1.2% apigenin content.

What foods contain apigenin?

Apigenin can be found in many fruits, vegetables and herbs, including parsley, celery, celeriac, red and white sorghum, tarragon, yarrow, basil, rutabagas, oranges, kumquats, onions, wheat sprouts, thyme, spearmint, and cilantro.

While many foods contain apigenin, parsley is a great way to get high amounts of it. Dried parsley typically contains about 45 mg/gram, and dried chamomile flowers contain about 3-5 mg/gram of apigenin. The apigenin content of fresh parsley has been reported to be as high as 215.5 mg/100 grams. Green celery hearts can contain up to 19.1 mg/100 grams.

While studies are limited, and the wide range of foods containing apigenin make it hard to estimate an accurate dietary intake, it is likely somewhere in the region of 20-25 mg per day. Of course, this could be higher, especially among people whose diets  are mostly or completely plant based.

Apigenin supplement

Of course, like most flavonoids, the supplement industry is more than ready to sell you apigenin as a dietary supplement. Typical doses start around 50mg, though higher doses are also offered.

Apigenin in the context of insomnia

Chamomile tea has traditionally been used for relieving insomnia for many years. Its usage was so commonplace that researchers have studied its active molecules, which include apigenin.

A small study saw 34 chronically insomniac adults between 18-65 years old given chamomile flower extract, with at least 2.5 mg of apigenin [1]. The participants had experienced the condition for six months or longer and had a total daily sleep time of 6.5 hours or less.

The researchers found that there were no significant differences between the treatment and control groups. These included differences in total sleep time, sleep efficiency, sleep latency, wake after sleep onset, sleep quality, and number of times that they awakened during sleep.

While it did not appear to have an impact on sleep quality itself, the researchers did observe a modest improvement in daytime functioning. They concluded that chamomile may be useful to improve daytime functioning for people suffering from insomnia.

Apigenin for anxiety and depression

Chamomile has also been traditionally used for treating anxiety and depression. A randomized, long-term clinical trial for the treatment of generalized anxiety disorder (GAD), was initiated in 2016. The trial saw the administration of 1500 mg (500 mg capsules three times daily) of chamomile extract to trial participants.

179 participants initially took part in an open-label phase, a phase of the trial in which information is not withheld from trial participants, allowing them to know what they are taking. In the second phase, 93 participants were randomized to either 26 weeks of continued chamomile treatment or given a placebo in a double-blind study.

Participants taking chamomile extract were shown to have significantly lower anxiety levels than participants in the placebo group. The chamomile group also showed a reduction of body weight and mean arterial blood pressure. Chamomile appeared to be safe and had a significant effect on GAD symptoms.

A 2012 study saw chamomile extract used for the treatment of GAD in a randomized, double-blind, placebo-controlled trial. Chamomile extract with a 1.2% apigenin content was administered to trial participants with anxiety; co-morbid depression, or anxiety with a history of depression; and anxiety with no current or past depression.

The 57 participants were given either chamomile extract or a placebo. The results showed a significant reduction in total Hamilton Depression Rating Scale scores with chamomile treatment. This suggests that chamomile extract may have an antidepressant effect.

This is good news, as research shows that depression can have a negative impact on the rate at which we age. In fact, according to the popular biological aging clock GrimAge, a clock that can accurately predict life expectancy, a person’s GrimAge is accelerated in major depression.

Anti-inflammatory properties of apigenin

Historically, chamomile tea has been used as a way to reduce inflammation, so it is no surprise that apigenin promotes multiple anti-inflammatory pathways, including p38/MAPK and PI3K/Akt, and that apigenin prevents IKB kinase degradation, which proceeds proinflammatory NF-κB activation and reduces COX-2 activity [4-6].

Apigenin has been shown to increase the expression of antioxidant enzymes, including GSH-synthase, catalase, and superoxide dismutase (SOD) to combat cellular oxidative and electrophilic stress. Our own white blood cells produce SOD and other reactive oxygen species to kill bacteria. Apigenin boosts the expression of phase II enzyme-encoding genes by blocking the NADPH oxidase complex and its downstream target inflammatory genes via increasing expression of nuclear translocation of Nrf-2 [7-9].

Apigenin and NAD+

In the context of aging and metabolism, apigenin and quercetin are both shown to inhibit the activity of CD38 [10-11]. CD38 is an enzyme that consumes nicotinamide adenine dinucleotide (NAD+) in ever-increasing amounts as we get older. NAD+ is a coenzyme found in all living cells and is essential for cellular function, DNA repair, and life.

Animal studies have shown that mice bred to be deficient in CD38 enjoy increased protection from mitochondrial dysfunction and are resistant to diabetes as they age. This protective action is regulated via the mitochondrial sirtuin SIRT3. Mice treated with apigenin show an increased level of NAD+ and are resistant to the effects of high-fat diets [12].

Given that CD38 actively degrades both NAD+ and NMN, it may be a useful approach to use CD38 inhibitors such as apigenin to increase NAD+ levels rather than try to boost them with precursors. In other words, it is better to treat the cause of NAD+ loss rather than trying to compensate for it. You can learn more from Dr. Nichola Conlon about the intertwined nature of NAD+, CD38, and senescence in her article.

Apigenin side effects

Apigenin is considered safe when consumed in normal amounts through a diet rich in fruits, vegetables and herbs. However, supplement doses tend to deliver a significantly higher amount of apigenin than would be generally consumed via dietary means. Higher doses of apigenin can cause stomach discomfort, and you should cease using it immediately and consult your doctor should this occur.

Some people can also be allergic to chamomile tea or apigenin, so again, if you experience adverse side effects, you should stop taking it.

The future of apigenin

Despite there being a number of interesting animal studies on apigenin, there is currently a lack of human data beyond cell studies. There is no doubt more to learn about apigenin, including its possible utility as a senolytic or senomorphic, but more research is needed before we can make any conclusions regarding the geroprotective effects of apigenin.

Disclaimer

This article is only a very brief summary, is not intended as an exhaustive guide, and is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse apigenin supplements nor any product or supplement vendor, and all discussion here is for scientific interest.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Zick, S. M., Wright, B. D., Sen, A., & Arnedt, J. T. (2011). Preliminary examination of the efficacy and safety of a standardized chamomile extract for chronic primary insomnia: A randomized placebo-controlled pilot study. BMC complementary and alternative medicine, 11(1), 1-8.

[2] Mao, J. J., Xie, S. X., Keefe, J. R., Soeller, I., Li, Q. S., & Amsterdam, J. D. (2016). Long-term chamomile (Matricaria chamomilla L.) treatment for generalized anxiety disorder: A randomized clinical trial. Phytomedicine, 23(14), 1735-1742.

[3] Amsterdam, J. D., Shults, J., Soeller, I., Mao, J. J., Rockwell, K., & Newberg, A. B. (2012). Chamomile (Matricaria recutita) may have antidepressant activity in anxious depressed humans-an exploratory study. Alternative therapies in health and medicine, 18(5), 44.

[4] Lee, J. H., Zhou, H. Y., Cho, S. Y., Kim, Y. S., Lee, Y. S., & Jeong, C. S. (2007). Anti-inflammatory mechanisms of apigenin: inhibition of cyclooxygenase-2 expression, adhesion of monocytes to human umbilical vein endothelial cells, and expression of cellular adhesion molecules. Archives of pharmacal research, 30(10), 1318-1327.

[5] Lapchak, P. A., & Boitano, P. D. (2014). Effect of the pleiotropic drug CNB-001 on tissue plasminogen activator (tPA) protease activity in vitro: Support for combination therapy to treat acute ischemic stroke. Journal of neurology & neurophysiology, 5(4).

[6] Huang, C. H., Kuo, P. L., Hsu, Y. L., Chang, T. T., Tseng, H. I., Chu, Y. T., … & Hung, C. H. (2010). The natural flavonoid apigenin suppresses Th1-and Th2-related chemokine production by human monocyte THP-1 cells through mitogen-activated protein kinase pathways. Journal of medicinal food, 13(2), 391-398.

[7] Huang, C. S., Lii, C. K., Lin, A. H., Yeh, Y. W., Yao, H. T., Li, C. C., Wang, T. S., & Chen, H. W. (2013). Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2-dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes. Archives of toxicology, 87(1), 167–178. https://doi.org/10.1007/s00204-012-0913-4

[8] Telange, D. R., Patil, A. T., Pethe, A. M., Fegade, H., Anand, S., & Dave, V. S. (2017). Formulation and characterization of an apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and antioxidant potential. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 108, 36–49. https://doi.org/10.1016/j.ejps.2016.12.009

[9] Paredes-Gonzalez, X., Fuentes, F., Jeffery, S., Saw, C. L., Shu, L., Su, Z. Y., & Kong, A. N. (2015). Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharmaceutics & drug disposition, 36(7), 440–451. https://doi.org/10.1002/bdd.1956

[10] Camacho-Pereira, J., Tarragó, M. G., Chini, C. C., Nin, V., Escande, C., Warner, G. M., … & Chini, E. N. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell metabolism, 23(6), 1127-1139.

[11] Schultz, M. B., & Sinclair, D. A. (2016). Why NAD+ declines during aging: It’s destroyed. Cell metabolism, 23(6), 965-966.

[12] Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa, M. T., … & Chini, E. N. (2013). Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes, 62(4), 1084-1093.

Highlanders enjoy life extension, would you?

Who Wants to Live Forever?

A recent survey of adults in the US found that only about one-third would take a life extension pill if one were available [1]. These findings are about the same as those of an Australian survey a decade ago [2], highlighting the need for more effective life extension advocacy. 

A plurality opposed

To investigate public attitudes towards life extension, a pair of researchers at the University of Texas at Tyler and UT Southwestern Medical Center surveyed about 900 adults. Participants were asked, “If doctors developed a pill that enabled you to live forever at your current age, would you take it?” The researchers explain that this frame was designed to make the treatment seem legitimate, effective, and painless. Participants were also asked for the youngest and oldest age at which they would want to live forever.

The survey used three age cohorts for analysis. The youngest, aged 18-29, consisted of undergraduate psychology students, while the older two (60-84 and 85+) were “healthy, community-dwelling older adults.” The division of the older adults into two groups aimed to capture the different concerns about death and dying, since people in the younger-old adult group had not yet reached the average lifespan and could expect to live longer, while the older-old adults “likely has less of a temporal horizon,” as the authors put it.

The three age cohorts did not differ significantly in their responses to the first question. In each group, only about one-third of the participants said they would take the pill, about one-quarter were unsure, and the remainder – roughly half – said they would not take a life extension pill. 

There was a difference in their answers to the second question, with the youngest and oldest ages increasing with the age of the respondent. This isn’t worth dwelling on since such life extension technology isn’t within our grasp at the moment, but it is worth considering; as the authors note, this means that young adults might miss out by choosing to stop aging before they have reached the age that older adults consider optimal.

What gives us pause?

Unfortunately, this study didn’t investigate why many of the participants were opposed to taking a life extension pill, aside from the statement that “it is possible that individuals may have concerns about immortality that may outweigh their death anxiety.” However, the overall proportions are roughly consistent with those reported in a 2011 study of Australian adults, and that study did include questions to clarify participants’ reasoning.

In a survey of roughly 600 Australian adults in three age groups (18–30; 31–50; 51+), about 35% said that they would use a life extension technology if it were available. However, 65% of the respondents supported longevity research. Another way to look at these results is to say that of the people who supported the development of life extension technologies, 52% would actually use them, while 34% would not and the remainder were unsure.

By including questions on the survey about the moral and ethical issues about life extension, as well as its personal and societal harms and benefits, the researchers had collected data to help them disentangle this. They found that 58% of the participants thought that there were concerning moral or ethical issues surrounding life extension, nearly half (47.8%) believed that such technologies would do more harm than good to society, and 38.9% felt that taking life extension pills would cause them more personal harm than benefit.

Further analysis of the survey responses showed that the strongest predictors of an unwillingness to use life extension technology were negative personal expectations and greater concerns about the “naturalness” of such technologies. A partial explanation may be that life extension technologies (and research) may be perceived as more akin to enhancements than to treatments; surveys about pharmaceutical enhancements report a similar split – support for the research combined with an unwillingness to use them.

Introduction: Biomedical technology holds the promise of extending human life spans; however, little research has explored attitudes toward life extension. Methods: This survey asked young adults (n = 593), younger-old adults (n = 272), and older-old adults (n = 46) whether they would take a hypothetical life extension treatment as well as the youngest and oldest age at which they would wish to live forever. Results: Age cohorts did not vary in their willingness to use life extension; however, in all three age cohorts, a plurality indicated that they would not use it. Men indicated a higher level of willingness to use the life extension treatment than women. Younger-old and older-old adults indicated that they would prefer to live permanently at an older age than younger adults. Discussion: If a life extension treatment were to become available that effectively stopped aging, young adults may be likely to use such a treatment to avoid reaching the ages at which older cohorts say they would prefer to live forever.

Conclusion

Research never happens in a vacuum. Understanding the attitude of the public towards life extension technology is vital both to secure support for longevity research and, in the long run, to ensure that any resulting technologies are  used effectively. Based on these two surveys, the past decade has not seen an upswell of support for life extension, despite continued advocacy efforts. Such analyses can also guide advocacy efforts by identifying concerns that need to be addressed: for example, discovering why many people feel that life extension would cause them more personal harm than benefit. Proponents of longevity should try to understand the basis for such concerns and address them.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Barnett, MD and Helphrey, JH. Who wants to live forever? Age cohort differences in attitudes towards life extension. Journal of Aging Studies (2021), doi: 10.1016/j.jaging.2021.100931

[2] Partridge, B, Lucke, J, Bartlett, H, and Hall, W. Public attitudes towards human life extension by intervening in aging. Journal of Aging Studies (2011), doi: 10.1016/j.jaging.2010.08.012

Death Clock

The “Death is Inevitable, Why Bother?” Argument

It might be inevitable that everyone dies eventually, but that doesn’t actually matter as to whether or not rejuvenation is worth pursuing.

Getting to the heart of this particular argument against life extension

There’s a fundamental similarity between the questions “Why rejuvenate your body if it’s going to die anyway one day?” and “Why clean your house if it’s going to crumble to dust one day?” An obvious answer to the latter question would be: “Because in the meantime, I’m going to live in that house, and for as long as I do, I’d like it to be clean.” This makes for a pretty accurate answer to the first question as well, so long as you replace “house” with “body”.

The implied assumption behind this concept seems to be that, as long as life doesn’t last forever, improving its quality and quantity is pointless. (It doesn’t make much sense to distinguish between quality and quantity in the case of life, because as we have discussed elsewhere, it really isn’t possible to extend the average lifespan without significantly improving health and vice versa.)

If this assumption were true, it would also apply to many other commonplace things and situations that we wouldn’t ever dream of considering pointless: if death is inevitable, why get a flu shot? If death is inevitable, why undergo heart surgery? If death is inevitable, why looking before crossing the street? If death is inevitable, why eat? And so on.

Even if death is inevitable, that is no reason not to develop life extension technology

The answer to all these questions is the same: for as long as we’re going to be alive, we’d like to make our lives as enjoyable as possible; and not only do all those things improve the quality of our lives, they make our lives last longer than they would otherwise. Maybe it won’t last forever, but a longer, more enjoyable life seems preferable to a shorter, more unpleasant life.

As an extreme example, if improving and extending a finite life is pointless, then since the universe seems doomed to die in one way or another, perpetuating the human race and improving the lives of its members is also pointless, which would be a seriously pessimistic outlook on life.

If life is finite, there’s no reason to make it shorter than it has to be, and, moreover, there’s no reason to make it less pleasant than it could be. If rejuvenation biotechnologies reached their full potential, we could be able to always enjoy youthful health no matter our age for as long as we live, however long that may be. Regardless of this length, there is no reason why the final years of our lives should be spent in the company of disease and decrepitude.

If, one day, the Big Crunch or something else comes to put an end to our lives, so be it. Death of the universe preceded by good health sounds like a better deal than the death of the universe preceded by cataracts, for example. At least we’ll be able to see what’s going on!

Mikhail Batin from Openlongevity

Building Support for the War Against Aging

The life extension community has a number of long serving people in its ranks, and one of the longest-active of those in Russia is Mikhail Batin. His activities go way back to 2008 when the non-profit organization Science for Life Extension Foundation, which was first created with the mission to support scientific research to develop life extension techniques.

Since those early days, Mikhail also went on to co-found Open Longevity with longevity advocate Anastasia Egorova, and this is where he is most active and focusing his efforts now.

Open Longevity is a non-profit organization that emphasizes the importance of complete transparency in aging research.  The team is currently focused on three areas:

  • Open projects (including citizen science)
  • Databases (creating new ones, such as Open Genes, and improving existing ones)
  • Overall biotech industry analysis as a way of analyzing the longevity field in particular and building ground for a better strategy for the life extension community.

Today, we would like to share an interview with Mikhail that was translated from the original, which appeared recently in Republic Online Magazine.

How can you live longer?

It’s a simple question. One that has a simple answer or, rather, a myriad of simple answers. Healthy lifestyle habits. Digital healthy lifestyle habits. Technology to monitor multiple health markers. In a nutshell, we have to sleep well, exercise for an hour a day and live as far from Antarctica as possible. Having said that, this simple advice comes with a lot of nuances and refinements.

There are hundreds of anti-aging clinics around the world. I think the only good thing about them is that they distract people from eating by keeping them busy with essentially useless procedures. The real gold comes from physical exercise, reduced calories, and a calm daily regime.

On paper I’ve just answered your question, but in all honesty I haven’t.

My answer was very superficial. Just as easily, I could have advised you to become extraordinarily rich and purchase the fountain of youth. Or, rather, you could try and build this fountain by employing thousands of scientists to work tirelessly at your behest.

Furthermore, by focusing merely on a healthy lifestyle, we lose sight of other dimensions of the issue. We get derailed in comparing different healthy lifestyle methods and lose sight of the bigger picture—a truly large-scale solution. That is what I would like to focus on here. There’s a legion of health specialists out there who can elaborate on the topic of healthy lifestyles without my two cents.

Preventative medicine suffers from any lack of consolidated peer review or general guidelines for clinical trials. Frankly, the word “nutritionist” makes me sick to my stomach. I have yet to see any quality peer-reviewed papers on the subject of nutrition.

If we were to discuss nutrition, I would suggest organizing and participating in large-scale clinical trials of any given healthy lifestyle fad. This would enable us to collect large amounts of useful data about aging. The details of this trial would be scope for a separate interview in itself.

Our general anxiety about our health leads us to look for immediate and practical solutions. This is a trap that breeds ample customers for the market of useless supplements, hydrolyzed placental protein and other so-called “wellness” clinics.

I would like to highlight the fact that at present we are discussing the wellness of a generally healthy person, whose health deteriorates with age.

Let us finally leave the subject of “wellness”. The next point in our discussion is the fact that our lifespan depends on the quality of medicine and the speed of technological progress in general.

Unless there is a nuclear holocaust, we are all destined to get some sort of age-related illness. So, let me reframe the question somewhat: is there anything we can do today to outsmart the impending deadly illness by the time it arrives. Is there a way to prevent it from becoming lethal? Perhaps there will be a vaccine or certain prophylactic measures put in place. It would be great if preventative healthcare could learn to reverse the process of aging.

When we think about tackling aging, we find ourselves between the world of uncertainty and the world of endless tools and possibilities. The next step is to choose which of these tools we can use.

However, before we begin trying to change the world for the better, before we create a world without illness or suffering, we must first answer one question: who is this “we” exactly? We all have different capabilities and skills. Who exactly will tackle the issue of longevity? If we don’t decide on the “we”, this issue will remain in the realm of ideas and good intentions.

We could make a large list of necessary clinical trials, forgetting to answer one simple question: who will sponsor them?

Alternatively, we could say that the government should allocate a budget for the study of longevity. Having said that, we should be aware that the government already has its hands full with other important tasks.

Progress comes from money. It is not at all clear where we can find a superhuman who will not only raise awareness about the issue of aging but also get hundreds of billions of investment into, let’s say, regenerative medicine.

What about something simple like longevity-related promotional and educational content for Youtube? Who will create such content? Who has enough skills and funds for its production and promotion?

It comes down to this: when we ask ourselves who exactly is it that can make a change regarding the issue of longevity? No single human can overcome death alone. No amount of talent or initiative is enough to overcome social inertia. No one man.

United, however, the most regular people can achieve anything they want. This is not a novel idea. I credit Nikolay Fedorov way back in the 1900s for developing this concept in his work “Philosophy of the common cause”.

Every generation faces the same challenge: will they be able to unite against death? So far year in and year out people have failed at this task.

The so-called “blue zones”, areas where people live longer, are a credit to these very people themselves. They have organised a lifestyle that is conducive to longevity. Loma Linda in the US is a particularly interesting case. It has a very heterogeneous population: diverse in character, not in genetic make up. Their lifespan is 10 years above the US national average. This is an example of “accidental” cooperation in favor of longevity. It is our job to turn this “accident” into a large-scale, purposeful endeavor.

Part of the answer to longevity is to surround yourself with other people who are interested in your existence. To develop and test large-scale instruments of cooperation in favor of radical life extension.

Let me suggest some of these potential tools. Or rather some of the necessary tools:

  • Open Source projects analyzing and collecting data regarding aging and longevity;
  • Clinical trials based on patients’ initiative;
  • Longevity Valley or Immortality Vale (an area similar to Silicon Valley that specializes primarily on life extension);
  • Open and affordable education in biology and all sciences pertaining to life extension;
  • Government lobbies for research programs on aging and longevity.

In terms of sciences I would single out the following research:

  • Chronic inflammation
  • Mitochondrial dysfunction
  • Epigenetic rollback
  • Damage to longer-lived molecules in the body
  • The body’s ability to respond to stress
  • Sleep
  • Activity of transposons
  • Gene therapy
  • Comparative evolutionary biology of aging

These are overlapping fields. In truth, there are many ways to achieve longevity. However, it is a costly quest, one that holds no guarantees. On the other hand, a timely death is 100% guaranteed if we continue to do nothing.

Chew on this for a moment, barring Qin Shi Huang—the founder and first emperor of unified China—no one, nowhere, not a single country in the world has made life extension a government priority.

As far as governments are concerned, people are all equal and, in general, mutually replaceable. In fact, governments are founded on this disregard of individual human life.

It is enough to ignore what governments proclaim and to look at actual budget allocation. It becomes self-evident that saving lives is not of utmost priority.

“How to live longer?”—in brief, we must build a new society.

Is life extension an achievable goal?

Any scientist worth his salt working in the field of aging will be the first to tell you that radical life extension is possible. They make no hard and fast promises, but they definitely see potential in this endeavor.

We have inspiring proof in the form of life extensions of laboratory animals. Furthermore, there is no physical law that we must overcome to achieve the same result in humans.

What can I say; evolution is excellent at creating “life extension”. Life expectancy within a species can differ 20 times, and between species—in the millions.

Man is learning to do many things better than evolution itself. Just look at the creation of the wheel, not to mention space exploration.

I began to notice hundreds of biotech startups, mostly in California, primarily targeting mechanisms closely related to aging. I don’t believe any of them will be successful in creating the “elixir of immortality”. However, their mere existence is a good sign. They can act as initiators of large-scale governmental programs, although I would be delighted if free enterprises were able to tackle this exceedingly difficult task.

To state the obvious, the best argument in favor of potential radical life extension would be the very act of radical life extension itself. However, at the moment, we are just at the initial stages of data collection, creation and testing of theories. The scale of these current endeavours is dwarfed by the enormity of the task.

We are nowhere close to having done everything possible to extend the lives of the maximum number of people for the longest period possible. This fact is irrefutable. Many scientists failed to conduct experiments due to lack of funds. Others left science altogether. The number of Master’s and Ph.D. programs in the biology of aging is insignificant.

On the other hand, it would be dangerous to underestimate the enormity of the task itself. There is no simple solution to aging and there cannot be one. It could very well be possible that the solution to aging is comparable in its complexity to terraforming on Mars.

It could even end up to be an insurmountable task. But wouldn’t it be nice to know this for sure? Our folly is that we are not even trying to find out if we stand a chance at all.

What are the biggest obstacles in the war against aging?

Here we face the Great Wall of Death as a derivative of human culture itself. Throughout our history, humans have been aware of our mortality and have tried to come to terms with it. In a way, the fight against aging is absolutely counter culture. It suggests putting all our plans aside and solely focusing on fighting death. This is very similar to what Nietzsche said about the creation of the superman.

The idea of immortality goes against all our traditions, rituals, and stereotypical behaviors. I can name a hundred reasons why we are moving so slowly. Let me elaborate on one: people don’t believe they can live long enough to witness the technologies of radical life extension. They don’t believe that any of this can depend on them.

It is just easier to not dwell on dying. It is easier to take the familiar beaten path of death.

The fight for life is not a question of faith. It is a game of low odds but with incredibly high gains. Mathematical expectation will be on your side if you value your life high enough. Don’t you find it strange that I find myself having to talk people into paying attention to life extension?

In regards to our biological makeup, the hard part is that we are made much like a disposable, useless thing, whose single evolutionary task is to spread its genetic material and disappear.

This likens our personality to a kind of parasite that resists the power of its own genome. So far, we are not even sure what exactly this personality, that we are trying to save from death, really is. We are as yet not aware of how our inner experiences work.

Yet another necessary task is the modeling of our brain functions.

What exactly do you do, and what are the aims of Open Longevity?

We are always trying to understand what is the most important thing we can do to increase research.

First and foremost, we are a conscription service: we recruit people to fight death. We create and distribute a lot of content egging people on towards action. This creates a lot of mutual or independent projects. It’s a growing field.

In a sense, we are old fashioned and believe in the power of books to change the world. I hope to soon see the publication of our work “Aging: it’s complicated”.

In the realms of science, we are interested in targets that can be manipulated to retard aging. Our next priority is the creation of an open database focused on aging.

By the way, the fight for longevity has its own trends. Last season was cellular senescence. Today it is transposons, which we are also interested in.

However, first and foremost, we are looking for future project leaders. Not so much in the fields of research as in projects aimed at changing public opinion and mentality.

What’s happening in the field of anti-aging at the moment?

A lot, actually.

There are quite large-scale efforts to create a method to diagnose aging. After all, we need to understand this process in a numerical format. We must have a reliable system for measuring age-related changes. The priority here today lies in various epigenetic clocks (a set of epigenetic DNA tags that can determine the biological age of a tissue, cell, or organ).

These diagnostics-related ideas breed a host of various advisory services. Instagram is littered with advice on rejuvenation. Occasional accounts even reference scientific articles. None of it looks particularly salubrious. There are no large-scale human clinical trials that can confirm or disprove the veracity of this advice. There are no consolidated opinions from the medical profession, nor are there any clinical recommendations. It’s necessary for us to first and foremost agree on standards for diagnostic tools and preventative medicine.

The number of applications for mobile devices and various health-related gadgets is growing exponentially. Obviously, collecting and processing an avalanche of new data will bring tangible benefits. You don’t have to be a big futurist to assume that disease prevention gamification is the next big step.

The emergence of longevity tech is another important trend. A hundred biotech startups with capital ranging from $10M to $3B have addressed hot topics in aging and are conducting clinical research.

Gene therapy and molecular design are gaining ground. The idea behind molecular design is to come up with unusual molecules with desired properties. For example, we need to come up with new ways to get rid of the crosslinks in collagen.

Also, I really hope that aging will soon attract people and technologies from the field of cancer research.

HARPA (Health Advanced Research Projects Agency) is a wonderful new initiative of this year, and it would be great to have this in healthcare. Perhaps the US Congress will give them $6.5B.

By the way, I can recommend the book “Immortality, Inc”. There’s quite a fascinating description of how the smartest and richest people came to grips with death. Surprisingly, the leaders of Google and Amazon are in on it.

Longevity lacks good big data. Therefore, I like the INSPIRE project, which aims to collect functional and omics data on aging and create a biobank in France.

Singapore has announced a life extension program, but little has been heard of it since.

As usual, there are some technologies which carry hopes for a slight increase in life expectancy. For example, transfusion of young blood plasma with albumin solution. However, putting one’s hopes on simple solutions is not worthwhile.

What tasks do you think are most pressing?

Today, it’s blockers of retrotransposons and inhibitors of reverse transcriptase. I will name a couple more areas: blockers, antibodies to oxidized phospholipids; fatty acid synthase inhibitors; we have yet to hear the last word regarding the field of senolytics and senomorphics.

Senolytics are drugs designed to kill senescent cells that interfere with the normal functioning of tissues. Senomorphics are drugs designed to act indirectly, blocking the actions of senescent cells.

Decaying cells were almost unknown to science 15 years ago. Today, not only are they being studied, approaches have already been proposed to block this aging mechanism. Let me say a few words about the three most unexpected solutions that have emerged over the past three years.

In the first case, American oncologist Scott Lowe and his colleagues used specially modified immune T cells to remove senescent cells, which express the so-called chimeric antigen receptor (CAR). As a result, they got the very same CAR-T cells that are now much talked about in professional circles.

Previously, they were actively used in immuno-oncology to remove degenerated cells. Now we are seeing a real boom in clinical research on CAR-T cells. According to ClinicalTrials.gov, several hundred clinical trials of related therapies are underway. Since the end of the 90s, there have been 5 generations of CAR-T cells designed.

Now, CAR-T cells have been successfully tested by oncologists as senolytics.

In the second case, scientists have shown the ability of extracellular vesicles to fight senescence. Vesicles are bubbles surrounded by a membrane. They are secreted by cells, in large numbers by stem cells.

Today, these vesicles are very actively studied as therapeutic agents for the transfer of healthy biological cargo, proteins, nucleic acids, and low-molecular-weight drugs. Their recently described role in senescence is interesting.

Back in 2019, English and Spanish scientists described how decrepit cells secrete vesicles with the IFITM3 protein, which literally infect normal cells with senescence, causing them to age.

There was a recently published study about the reverse process: vesicles from young cells reduced cellular aging in an old body, reducing lipid peroxidation. The key molecule carried by the “young” vesicles was the antioxidant enzyme GSTM2, a large amount of which is characteristic of long-lived species, for example, naked mole rats.

Before that, in 2019, there was the work of American biologists from Johns Hopkins University. They found an important antioxidant enzyme, peroxiredoxin, in extracellular vesicles from induced pluripotent stem cells (iPSCs). Most importantly, iPSCs are champions in the number of extracellular vesicles. They secreted them almost 20 times more than the other type of stem cells, the mesenchymal.

In my view, vesicle therapy is likely to become a fundamental new type of therapy.

The third approach to combat senescence was described quite recently, in May of this year. The Americans from the University of California were able to activate special immune cells that fight aging—invariant natural killer T cells (NK cells).

Tested in two animal models, obese mice with fibrosis, the activation used alpha-galactosylceramide (a-GalCer), a well-known lipid antigen that specifically activates these immune cells.

As a result, senescent (decrepit) precursors of fat cells were removed in obese mice. This is a potential approach to fighting obesity in old age and to prevent the development of diabetes.

And in the fibrous model, cleansing from senescent epithelial and mesenchymal cells led to a slowdown in profibrotic processes. This will allow virtually all older tissues to perform better.

I have just considered a small but important topic in aging—the fact that cells become decrepit and damage tissues and that cells can be cleaned.

There is potential for new therapies here, but there is no single institute for the exclusive study of senescence, there is no single-state program—the study of aging is as yet terra incognita. Even Nature thinks so, publishing in May another article, “An aged immune system drives senescence and aging of solid organs”.

We will talk about scientific problems in more detail in our new book. Hopefully, it will come out this year.

The possibility of slowing it down or reversing human aging has been the focus of researchers for over a decade. What results have they achieved, and could it be possible in the near future to increase one’s youth by at least a few years?

We can say that this has been a hot topic for over a century, but, so far, there is no consensus on any issue. Even on the existence of aging itself, there is no consensus; maybe it is best to avoid using a term that could not even be defined?

When they say that aging is an increase of the likelihood of death, and they do not describe what happens physically, this reveals a lack of understanding of the very process.

It so happens that theories of aging follow the major discoveries in biology. They discovered immunity—there will be an immune theory of aging, hormones—the hormonal theory of aging, epigenetics—the epigenetic theory of aging.

Now, there are many works in the field of alternative splicing—we can totally put forward an isoform theory of aging in response.

At the same time, there are a lot of ethics involved in our understanding of aging: aging is something bad. It is a violation of physiological functions, a breakdown. Thus, aging begins to cover everything we know about the body. As a result, we begin to get bogged down in all this comprehensiveness.

Maybe, in order not to drown, we need to focus our attention on something: here is a chronic non-infectious inflammation, let’s study it and do something with it; here is mitochondrial dysfunction, this subject is also clear; let’s lower the level of non-enzymatic glycation and see what happens.

I emphasize that we do not yet know which strategy will be the most effective. There are roughly twenty branches of aging studies, and our knowledge is increasing.

The science of aging has achieved the following: we have learned a lot and are more confused. Since the dominance of the oxidative theory of aging, there has been less clarity. We can say that our ignorance is growing exponentially.

Basically, you need to take the most important interventions of the past twenty years, from rapamycin to IGF-1 inhibitors, and ask yourself why they didn’t work? We need to focus on the inefficiencies and side effects of potential geroprotectors. What is it that is always in our way?

So far we have found out that a mouse is not a human and that 30% of life extension in mice does not carry over to humans. We need to understand why that is so.

At the same time, of course, we should avoid negative spell casting: “everything is so complicated, tangled and difficult”. Yes, it is difficult, but we must rush head on into this complexity. All knowledge about aging should be well structured.

Human stem cells for growing organs are beginning to be increasingly used in medicine. It is also likely that the depletion of stem cells is one reason we age, are there any methods that exist today that can address this problem?

You can add stem cells. The first bone marrow transplant was performed 62 years ago by Georges Mathé, a French oncologist, but these are alien cells, of course, and if you just inject donor stem cells, rejuvenation does not occur. What does occur is profiteering off gullible patients. I wonder why there are still no high-profile criminal trials in Los Angeles regarding all of these procedures.

As for organ growing, I think we need to focus on therapeutic cloning. That is, growing clones of our own organs. After all, we can roll back a cell to a pluripotent state, and if so, theoretically there exists a combination of influences, including various growth factors, enabling the desired organ to grow from this cell. Of course, a new generation of bio incubators will be required. Regenerative medicine needs to move in this direction.

Yes, stem cells are shrinking, and this is true aging. If we could effectively increase their quantity (without losing quality), this would be a solution to one of the problems of aging, blocking one of the harmful mechanisms. The problem is that the existing products on the market do something completely different: foreign stem cells almost never take root, even the host’s own cells rarely take root, since this process requires complex factors and conditions.

If such therapies do have an effect, then it is achieved due to the molecules secreted by these cells in those hours and days before they have died.

In particular, we are talking about the development of exosomal therapy. The cell can release into the surrounding space both free molecules and exosomes packed in special bubbles, also called vesicles (I have already spoken about them). Modern science is very interested in this delivery method. And by clinical research, I mean Longeron, not what is happening in the Bahamas, of course.

Perhaps there is a possibility of a non-trivial alternative approach. Aging is an extremely complex thing, and it is not yet clear how we can create a cocktail of drugs that prolong life. The idea is to try it out blindly. We need to organize and train a certain biological system that can have a suppressing effect on the aging of the body. Yes, the topic is quite speculative, but I think we need to go in this direction as well. Michael Levin suggests something similar.

When can we expect a cure for old age?

Let’s ask ourselves a question: what must happen before a cure for old age is found? Since the task is large-scale, probably some huge project should be created. When can this happen?

Let’s consider the arrival of billionaires in this field as a marker of progress. Their number is growing, but they are focused on commercial projects, which seems to me to be a mistake. At some point, I think the concept of radical openness will prevail in aging research. To be precise, I am sure of it. It is necessary to build such a schedule and see at what point in time there will be 100 major players.

It will probably take another 10 years to create a megaproject. Then 10 more years for us to extract the first results on human life extension from the colossal amount of data. It will be sometime 2040–2045. The very same dates coincide with the forecasts on the possible emergence of a strong AI.

I would turn the conversation from predictions of when we learn to extend a person’s life to talking about a plan to make it happen.

Who has the best plan in the world, and how long does it take to get it done? Calico? It seems unlikely, no. Facebook with its cell atlas? So far, no results have been heard of.

The clearest position has been and remains with Aubrey de Grey. Regardless of how we may feel about him, on the topic of aging, he is the most intelligible dude in the world. Until this year, he had a budget of $5M a year. When will he have 5 billion? This does not mean that it is he who will create the technology, but the budget of his SENS foundation is a marker of society’s attitude towards the fight against aging.

Creating a cure for old age is about implementing a clear plan, a clear strategy. Create a strategy, and you have a deadline.

This is a very important thought: we need to be clear about the chain of events that must occur before the creation of technologies for radical life extension. It is on them that we must focus our attention. Let’s say we believe that a cure for old age cannot be created without a major international project.

This means that in, let’s say, the EU itself, some political processes must take place that will lead to the expansion of the Horizon program. What could drive such an initiative? First and foremost, civic engagement.

What steps do you think should be prioritized?

A large part of the fight against aging is in the collection of databases. If we are talking about the control of genes over lifespan, then we must have all these “lifespan” genes collected. We carry out a small part of this work, although it is subject to criticism. They say it is impossible to formalize all knowledge about genes associated with aging. Our position is quite simple: let’s look at the whole picture, to the extent that it is available to us now. And then we will see how useful it is, for example, in selecting a combination of potential geroprotectors.

All DAMP, SASP, changes in immunity, lipid, various omics data, cell atlas, and the actions of potential geroprotectors and their side effects must also be transferred to the databases. Transcriptomes of different tissues of people, of different ages.

Datasets are needed to develop diagnostics of aging to understand the early pathogenesis of age-related diseases. We need open data on human aging.

As I said, the fight against aging is about getting good new data and careful processing of the data that has already been obtained. In particular, we need data on changes in the transcriptomes of every human organ, in different ages. Such work has not yet been carried out anywhere in the world. It costs several hundred million dollars. But without it, we would not know how a person grows old. It must be an open dataset. Who will pay for this? Who will pay for open-source aging projects? For all the primary data to be published and not to be under any patent protection.

I think, without open-source projects, we will not be able to revolutionize aging.

Why so categorical? Doesn’t the current system of thousands of pharmaceutical and biotechnological companies work on prolonging human life?

Of course they do. Research is ongoing on all fronts. If the technologies that are now being created in the fight against tumors can be used in the partial removal of senescent cells, and these, in turn, still turn out to be a serious cause of aging, then this will be a breakthrough. The same goes for epigenetic retracement. Pharma is working, and we are closely monitoring everything that happens, but we want more. What approach can overtake all biotech? Open data. Then there will be no hiding of data due to commercial interests, and we will have an increase in the speed of development and the level of expertise on what needs to be done in the first place.

We will proceed thusly: We initiate an open non-profit project in aging that we will declare as being the best. This will be true because it will be one of a kind. Then, we will propose others to create a project that would be better. Perhaps we will announce a prize. Thus, we want to launch an avalanche of non-commercial projects.

The point is that life extension is valuable in itself. It’s nice to make money, of course, but it’s better to stay alive. Therefore, we need to remove this weight of compulsory commercialization. Korolyov would not have launched Gagarin into space if he was required to pay off the flight around Earth.

Our task is to convince philanthropists that this approach is correct. The amount of money in a non-profit approach is generated from the number of volunteers who are willing to spend their personal time on the goals and objectives of the NGO. We have a big-enough problem here. Research on aging itself requires a lot of knowledge. This is not a volunteer garbage collection, when everyone can go clean up the park. We want volunteers to perform non-trivial tasks. What solutions can there be?

Raising awareness of how aging works. Timofey Glinin gave 12 lectures on the biology of aging and posted them on YouTube. There should be a thousand lectures of such that would most fully cover the field of aging research. There should be a unified course following the example of the Khan Academy.

Another approach could be patient-driven clinical trials. Of course, it is not the patients themselves who should conduct the research, but initiate it, and the research would take place in an organized manner. Perhaps what is now called biohacking may turn into patient research.

Nevertheless there is still no strong solution out there for those who would like to invest their time into radical life extension. We have to keep on experimenting.

If aging is so difficult, are there alternative solutions? For example, organ growing?

There are many alternatives. For example, cyborgization of organs, artificial blood. We would get rid of half of the problems if we learned to artificially deliver oxygen and nutrients to the brain.

I think a head transplant, or rather a body transplant, is a good alternative. There is a rather important stage here: the maintenance of the vital activity of the head of a large mammal outside the body. It would be great to set a world record in this area. A simpler step is the exchange of circulatory systems between animals, so that the heart of one pumps blood for another. I wonder what would happen if these animals were clones.

Are such experiments ethical?

Let’s think about this. If we make the value of human life absolute, then inaction, missed opportunities to prolong life, becomes the true evil.

Religious figures often hide behind talk about bioethics in order to slow down progress. Just look at the ban on human cloning. Naturally, we should not clone a person if we are not sure that the clone will be healthy. But to prohibit cloning because of the assumption that a clone will not possess a soul is going too far.

Experiments on animals are a necessary evil, otherwise we would not have medicines and medical technologies.

You follow the ideas of Russian cosmists, who believed that in the future, people would be able to preserve their youth. How relevant are the ideas of Vernadsky and Tsiolkovsky in our time?

Talking about heritage. If today, we were to set up a major international conference on aging in Europe, attended by participants from many countries, do you know what the most frequently asked side question would be? Why are there so many Russians? 30% of the participants would be Russian speakers.

This is that kind of continuity. The Russians are very much in favor of the idea of ??physical immortality. We do not notice this in Russia, but actually we are very strong in transhumanism. I think that in the next few years, organizations with Russian roots will reveal themselves.

Who in the world do you think has come closest to life extension?

I don’t know about the result per se, but I began to like Sergey Young’s activity more. It is picking up momentum.

I would like to believe in Gero’s company, but I take it partially on faith, as I do not understand their complex physics.

Michael Greve from Germany announced today that he will invest $362M in rejuvenation startups. He comes across as the most competent investor in Europe.

Many scientists are doing interesting research.

I’ve just read Rochelle Buffenstein’s article on epitranscriptomics today. Another universe of aging research has been discovered.

Separately, I would mention the main fighters against protein crosslinking in the extracellular matrix, David Spiegel and Jonathan Clark. These stitches are one of the key barriers separating us from longevity. Extracellular matrix proteins are crosslinked by sugars and stop working normally. The matrix becomes rigid and triggers entire chain reactions of pathological processes associated with epigenetics, genomic instability, mitochondrial dysfunction, stem cell depletion, and more. Spiegel and Clark, with the support of Aubrey de Grey’s company, are actively studying this cross-linking of matrix proteins.

Last year, they managed to create an antibody that specifically binds to glucosepane, one of the main matrix cross-links. This will enable us to measure the amount of glucosepane in tissue.

A year earlier, Spiegel and his team tested the bacterial enzyme MnmC in action. Their work has shown positive results in breaking down two key glycation end products (AGEs) that also contribute to aging: carboxyethyl lysine and carboxymethyl lysine.

At the same time, we know that bacteria and fungi have a considerable evolutionary arsenal to combat AGEs: glycopeptides, metalloproteases, amadoriasis, and deglycases.

Let this be my refrain, but here too we need an institute, an international research program, and not just five laboratories with small budgets.

It is customary in our region to scold Calico, but I think they should finally be able to get somewhere with $3B.

You know, I also like what is happening in the Russian segment of Facebook on this subject. It seems to me that the right processes have been set in motion there, and wonderful collective intelligence is being created. I am one of the chefs in this kitchen of immortality. Subscribe to my Facebook account.

What advice would you give someone wanting to invest in life extension? How to choose a company, which fund to finance?

First of all, I would recommend spending 10% of the proposed investment on open research and on a non-profit approach. Or better, 100%.

Longevity startups are now dominated by an aggressively naive approach. These people believe they’ve caught God by the beard, so money is poured on simple solutions: like now we will remove bad cells or add a “longevity gene”. There is no lack of funding for this kind of approach. Any given Stanford professor promising to find a cure for old age sometime a little later, but for now needing to conduct clinical research on a different nosology, albeit closely related to the mechanism of aging, will easily find funding.

There is little money available for the establishment of cause-and-effect relationships in aging, for the evolutionary-comparative biology of aging, for open data on human aging.

You can make money off the hype, but is this what we want? We need true life extension.

Aging as a problem is huge. There is no need to worry that you will not have time to profit from selling the elixir of immortality. If you’re late and someone else is making money on radical life extension, that’s great. This means your life expectancy has increased. Now there is time for further enrichment.

Nevertheless, I admit that I could be mistaken, and it is businesses who will prove capable of creating at least a weak cure for old age. Perhaps the conditions for particular financing are as follows: either commerce or nothing.

Then we have to answer the question: what do we, as startups, know that Calico or Pfizer does not know? They have no problems with money, they have the best specialists, and they work all the time. What is our strength?

First of all, you need to invest in improving the competence of the analysts who work for you. A very strong American full-time professor costs $200–300K a year. There should be several such people working exclusively for you.

Second step. Use the stock exchange as a way to test your competence. If your team is focused on research related to inflammation, then you should probably pick up a good package on the NASDAQ by reading the results of clinical studies. In pretty much every direction, wherever you go, there are already listed companies working on similar tasks.

Third step. It sounds strange. Choose a totem animal. It is possible that evolution has already solved the problem that you are solving in prolonging life. Maybe learning how she did it for a particular organism will help you develop technology.

I also think that when investing, you need to keep a certain focus. Don’t get scattered into dozens of different directions, but invest in companies from the same sector working on similar tasks. This will increase the investor’s own competence. Yes, it is better to know one topic than spread yourself too thinly. On the other hand, avoid depending on one single company; work with several different ones.

So then what areas of investment seem more promising to you?

I naturally do not provide investment advice. I can only speculate about interesting research areas in which technology can be created.

We already mentioned splicing when we talked about the theories of aging. I should mention the main researcher of changes in splicing during aging, an English biologist Lorna Harries.

The story of splicing and aging began recently, in 2016, when several publications came out describing age-related changes in splicing in different species, from worms to humans. Before that, they already knew about the changes in splicing in various diseases.

What is splicing, and why is it important? RNA splicing is when introns and exons derived from a gene’s DNA sequence are removed and combined into the final RNA sequence from which the protein will then be synthesized.

Introns are usually discarded, exons remain. They can be shuffled in a clever way, making it possible to synthesize different proteins from a single gene. This is called alternative splicing.

All these processes are disrupted during aging, which, of course, negatively affects the functioning of the body, and, as studies show, it may be one of the causes of aging.

Despite the complexity and importance of this area in the fight against aging, only one team, led by Lorna Harries, is engaged in this research. The biotech startup SENISCA was created for this. I must say, they already have had some successes; they were able to identify the key molecular players in these aging processes.

Of course, in the naked mole rat, splicing processes are very stable throughout almost its entire life. How could we leave it out of this discussion?

Another team of scientists who are doing a lot in the fight against aging are the Spanish biologists Reinald Pamplona and his colleagues. They became known in the early 2000s as the first to show that limiting the amino acid methionine has a positive effect on health and longevity, and then they actively studied the processes of lipid peroxidation.

Lipid peroxidation is when the lipids of cell membranes attack free radicals. Then, chain reactions occur, when some oxidized molecules oxidize the next, and so on. The metabolites of these reactions can form the end products of glycation.

The most susceptible to lipid oxidation in membranes were polyunsaturated acids. Scientists have traced an interesting correlation. The less unsaturated docosahexaenoic omega-three fatty acid there is in the membranes, the longer the species lives.

So, in mice, this acid in the membranes was 9 times higher than in naked mole rats. Based on this data, Pamplona and colleagues have put forward their membrane theory of aging. This suggests that the composition of membrane fatty acids, through its effect on lipid peroxidation, is an important factor in life expectancy. It sets the pace of aging and links metabolism to longevity.

Fighting lipid oxidation is a very promising topic, and I think new blockbusters will be created here. In general, there are many areas of work.

You probably want me to name the tickers of all the promising companies? I need to think more about this. We are currently conducting an in-depth analysis of all the biotech companies associated with longevity

Am I correct in my understanding that you feel that the real culprit is the underfunding of academic science?

Academia too has its problems. Its structure is wildly archaic. It is like some sort of feudal slavery system. Graduate students from all over the world, young postdocs are humiliated. They essentially act as “science slaves” to their master, the “serious scientist”. Low wages, lack of freedom, and a strict hierarchy make 90% of people leave science.

We are left with a lucky 1% who happen to be good at marketing and self promotion and have an eye for legal subtlety.

Basically, by the age of 40, a scientist feels he’s been deceived: there’s few perspectives and a lot of lost hope. Academia’s efficiency is extremely low. The rat race for survival results in lots of trashy work; a lot of experiments cannot be reproduced in part because of false data that was supplied for the sake of receiving further funding.

Novel organisational solutions are the super task. A very good example is how Elon Musk created Neuralink.

There are still so many problems to solve. Do we even stand a chance?

In spite of all this, I am not only a longevity optimist, I also believe that we must strive for an unlimited lifespan, for the physical immortality of mankind. I believe in the incredible power of the human mind and the unquenchable desire to live. At the end of the day, the work of tens of thousands of people will bear fruit.

We need to closely monitor potential drivers of social processes. For example, it might be transhuman art. Art that evokes the desire to act in favor of extending the human potential.

As for the odds. We will stand a good chance when we have a good strategy. Look, the fight against aging is extremely difficult at the molecular level. But it is no less difficult at a social level. We need to press thousands of levers, spin millions of wheels of public order, to be able to radically change the situation in favor of prolonging life.

Enumeration won’t solve these tasks.

What is the current solution for raising funds? By increasing the amount of content related to scientific achievements. It is believed that people with resources will read a lot about aging and start spending private and public money. It is working, but not at all to the extent that we would like it to.

There are no strong longevity lobbyists in the world because no one pays for such work. Private funding goes to venture capital.

We need some sort of devious strategy. We must use the scientific method not only in the laboratory but also in the organization of social change. Here, we also need big data, but of a different nature: what role the struggle for life holds in public minds and what the factors that can influence public opinion are.

Now, these are the direct tasks of our organization, Open Longevity.

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