Longevity and DeSci Recap – November 2023 | Lifespan Research Institute

Date Posted: December 1, 2023

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Longevity and DeSci Recap – November 2023

Thanks for joining us again for the latest edition of the Longevity and DeSci Recap. This month’s highlights include fantastic conferences, such as the Rejuvenation Startup Summit 2024 in Berlin, the Vitalia event in Roatan, and the large-scale Longevity Med Summit in Lisbon, along with many other industry insights.

Upcoming conferences

Join the Rejuvenation Startup Summit 2024 this spring: The proclaimed world’s largest in-person longevity startup gathering is coming this spring. From May 10-11, longevity startups, founders, investors, and researchers from all over the world will join together in Berlin to discuss longevity and the future of the industry in what’s sure to be an exciting event.

The previous Summit, held in 2022, attracted more than 400 participants from 30 countries, making it an interesting networking opportunity. The conference organizers have just announced the first set of expert speakers to include Michael Greve, the founder of the Former Healthy Foundation, Matthew Rosen of CoRegan, Alexander Leutner of cellblocks, and, of course, Lifespan’s own Stephanie Dainow, among many others. Follow this link to book your tickets.

Vitalia longevity popup event approaching: Following the success of the world’s first longevity popup city event, Zuzalu announced another exciting longevity gathering has been announced, and it’s approaching fast. This January will see the launch of Vitalia, an initiative to start a longevity network society, aimed at improving the human lifespan. The event is set to run over two months from January 6, 2024 to March 1, 2024 in Roatan.

Don’t miss the Longevity Med Summit 2024: On May 8-9, 2024, longevity experts and enthusiasts from around the world will gather in sunny Lisbon, Portugal for the much-anticipated Longevity Med Summit. Participants of the conference can look forward to a comprehensive agenda packed with presentations, discussion, and networking opportunities centered around such topics as functional medicine, AI and digital technologies, and regenerative medicine. Tickets for the event are still available for purchase from the website with a variety of options.

Longevity investment and development news

The $101 Million prize pot for longevity solutions: XPRIZE Healthspan has just announced the launch of a truly massive prize for a longevity-focused team that discovers and proves a “cost-effective therapeutic that restores muscle, cognition, and immune function by a minimum of 10 years”. The catch? The team that takes home the prize must demonstrate treatment results in a year or less. Entrants should bear in mind that although innovation is crucial, concerns for safety and standards for medical ethics should be applied at all times.

$38 Million in funding secured by Vivodyne AI-backed lab-organ testing: US biotech company, Vivodyne, just announced the success of its seed funding round in raising a total $38 million led by Khosla Ventures. This newly-raised capital is set to boost the development of its predictive drug platform, based on AI-technology, that is said to be able to provide preclinical data even faster, ensuring sustainable, accurate, and reproducible results.

The company, founded by University of Pennsylvania bioengineers Andrei Georgescu and Dan Huh, works by using robots to grow 3D human organ models for drug testing, backed by its AI platform. These lab-grown organs are said to be capable of mimicking human functions and phenotypes, and are key to Vivodyne’s ability to produce scalable, realistic preclinical data rapidly. Currently, the company’s platform is able to handle over 8,000 tissues simultaneously, which is more than any of its competitors.

€21 Million for Al-backed Alzheimer’s project: PREDICTOM, an AI initiative focused on Alzheimer’s detection, has just secured €21 million for an early-interment AI project designed to predict Alzheimer’s disease. With dementia cases rising across the EU, the platform is designed to collect biomarkers from patients at home, use AI algorithms to generate their risk, and, hopefully, make an earlier diagnosis leading to improved long-term longevity results.

Tech breakthroughs & new research

Turn Bio unveils targeted mRNA delivery solution: mRNA medicine innovator Turn Bio has just announced a new advancement in the treatment of age-related skin conditions. By utilizing its proprietary eTurna lipid nanoparticle delivery platform, the company is able to reach dermal fibroblasts without damage to other organs, marking a new level of precision in dermatology and a new potential market offering for clinicians and patients.

DAOs and communities

Opportunities for better crypto governance: This November saw Changpeng Zhao, the founder of world-known cryptocurrency platform Binance, step down from the position of CEO amid the company’s legal battles and admission of guilt in the violation of anti-money laundering laws. As sentencing commences for the former CEO, who is ordered to remain on US soil for the duration, many in the crypto world, such as Coinbase CEO and NewLimit founder, Brian Armstrong, see this as an opportunity to build legitimacy for cryptocurrency as an immensely popular fiat alternative. Seeing it as a way to “turn the page”, Armstrong expresses how crypto companies are changing the world and why acceptance and regulation is a big part of it.

VitaDAO launches new member portal: The DAO that never stops innovating has just dropped its latest creation online: the VitaDAO member portal. Designed to make interacting with the DAO easier and more user-friendly, the portal will contain an overview of a VitaDAO member’s activities with the DAO, including $VITA holdings and governance proposals, allowing more control and insights into the DAO for members.

World Longevity News

Unmasked: who is @agingdoc1?: After much speculation, the notable anti-aging figure @agingdoc1 on X (formerly Twitter) has finally been revealed as David Barzilai, a Boston-based MD and PhD with a slew of qualifications to his name. Barzilai’s account has long been known for its fascinating longevity insights into aging-related studies, which he revealed to be a result of personal research and the desire to share it with a wider audience. So, what’s next for Barzilai now that the great longevity secret – aside from the fountain of youth, that is – is out of the bag? @agingdoc1 is heading to YouTube and starting a podcast series on aging; keep watching to find out more.

Social media pages to follow this month

David Barzilai X – The star of this month’s social media has to be no other than @agingdoc1.

David Sinclair X – One of the best-known names in the longevity world and a must-follow on X.

Vincent Weisser X – Key member in building longevity DAOs, such as VitaDAO, Molecule, BioXYZ, and CryoDAO.

Date Posted: December 1, 2023

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Healthy Diet Linked to Massive Gains in Life Expectancy

A new study has found that switching to longevity-associated dietary patterns was associated with up to a 10-year gain in life expectancy for 40-year-olds and up to a 3.4-year gain for 70-year-olds [1].

Eat your way to longevity

Since the early twentieth century, average human life expectancy has risen enormously due to factors such as advances in medicine, decrease in poverty, and better sanitation. However, in the recent couple of decades, this progress has become much slower and even reversed its course in some countries, including the US [2].

One reason is that most of the initial impressive gains were due to a decrease in infant mortality and in the prevalence and deadliness of infectious diseases. Another is that it is notoriously hard to keep humans alive during the latest few years of their lives, when they are attacked by several age-related diseases simultaneously. According to estimates, eradicating cancer alone, which still seems like an impossible feat, would only increase the average life expectancy by about three years.

This illustrates the limitations of the traditional healthcare approach of fighting singular diseases after the symptoms appear. Geroscience, on the other hand, advocates for treating the underlying processes of aging, thus delaying the onset of numerous age-related diseases at once.

While geroscience sits on the cutting edge of biology, currently, the most effective arrows in its quiver are lifestyle interventions, such as dietary changes. What you eat and when you eat it can have a profound effect on your health. Therefore, it may be possible to estimate how effective dietary changes are in extending lives.

The naughty and the nice

This is what a new study from an international team of scientists, published in Nature Food, attempts to do. Using data from the UK Databank, a vast repository of biomedical data on half a million British citizens, the researchers identified “longevity-associated dietary patterns” by dividing consumption levels of several food groups into quintiles and calculating hazard ratios: here, the mortality odds for quintiles 2-5 compared to the lowest quintile.

In this image, red designates the unhealthiest patterns, green shows the healthiest ones, and blue is for the current recommendations from NHS’ Eatwell Guide. The two dark green rectangles, according to the researchers, “had large uncertainties”.

The results suggest that the longevity-associated dietary pattern includes a moderate intake of whole grains, fruit, fish, and white meat; a high intake of milk and dairy, vegetables, nuts and legumes; and a relatively low intake of eggs, red meat, refined grain, processed meat, and sugar-sweetened beverages.

However, the effect sizes differed significantly. The two “deadliest” types of food were processed meat and sugary beverages (which is in line with existing research) [3], while for red meat, the positive association with mortality was more attenuated. It is not always better to eat plenty or none of a certain food. Sometimes, the sweet spot seems to lie between those two extremes.

The model was adjusted for age, sex, socio-demographic area, smoking, alcohol consumption, and activity level. Further adjustment for body mass index and energy consumption showed slight reductions in inverse associations with mortality for whole grains, vegetables and fruits, a small reduction in risk from red meat, and stronger inverse associations for nuts and white meat.

Up to 10.4 additional years of life

The researchers then calculated average gains in life expectancy associated with switching to either Eatwell guidelines or the healthiest patterns. For a 40-year-old, switching from the median dietary pattern to the healthiest one was associated with a 3.1-year increase in life expectancy for females and a 3.4-year increase for males. Gains from switching to Eatwell guidelines were much smaller (1.3 and 1.4 years, respectively). The effect of switching to longevity-associated dietary patterns from particularly unhealthy ones was massive: 10.4 years for females and 10.8 years for males. Equally impressive, if initiated at the age of 70, such a change was still associated with more than a 5-year increase in life expectancy.

While populational nutritional studies are notoriously hard to interpret and can only establish correlation and not causation, this is our best tool to estimate the effect of dietary patterns on longevity, since longevity-focused randomized controlled trials are all but impossible. Reassuringly, the growing amount of data seems to point in one direction: a balanced healthy diet can greatly increase your chances of living longer, even if adopted later in life.

In conclusion, for middle-aged adults in the United Kingdom, sustained dietary improvement is predicted to increase life expectancy by about 3 years for both females and males. Importantly, for those with the least healthy dietary patterns, change to the longevity-associated dietary pattern is predicted to translate into approximately 10 years gain in life expectancy. Changing from an unhealthy dietary pattern to eating in line with the Eatwell Guide was associated with an 8 year life expectancy gain. Gains in life expectancy are lower the longer the delay in the initiation of dietary improvements, but even for those initiating dietary change at age 70 years, the gain in life expectancy is about half of that achieved by 40-year-old adults.

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Literature

[1] Fadnes, L. T., Celis-Morales, C., Økland, J. M., Parra-Soto, S., Livingstone, K. M., Ho, F. K., … & Mathers, J. C. (2023). Life expectancy can increase by up to 10 years following sustained shifts towards healthier diets in the United Kingdom. Nature Food, 4(11), 961-965.

[2] Venkataramani, A. S., O’Brien, R., & Tsai, A. C. (2021). Declining life expectancy in the United States: the need for social policy as health policy. JaMa, 325(7), 621-622.

[3] Larsson, S. C., & Orsini, N. (2014). Red meat and processed meat consumption and all-cause mortality: a meta-analysis. American journal of epidemiology, 179(3), 282-289.

Date Posted: December 1, 2023

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Rejuvenation Roundup November 2023

As researchers and biotech companies continue to work on the therapies and technologies that may let people live longer lives, much other research tells us about the lifestyle habits that people are doing to lengthen them – or shorten them – in the meantime. Here’s what we’ve learned in November.

LEAF News

An Anonymous Longevity Enthusiast Unmasks Himself: A prolific anonymous poster who became popular in the longevity community has revealed his identity, and other longevity luminaries have chimed in. Anonymity is seldom practiced in the longevity community.

Research Roundup

Bacteria from Alzheimer’s Patients Induced Symptoms in Rats: New research published in Brain investigated the influence of fecal microbiota transplants from Alzheimer’s patients on cognitive function and neurogenesis in rats and human cell cultures.

Hyperbaric Oxygen Therapy Improves Bone Health in Rats: Scientists have demonstrated that hyperbaric oxygen therapy can reverse some aspects of bone deterioration caused by aging and obesity in rats. This involves placing the patient in a chamber with elevated levels of oxygen and atmospheric pressure.

Predicting Future Frailty with an Epigenetic Clock: An accepted manuscript in the Journals of Gerontology has described how a third-generation epigenetic clock is a predictor of future frailty.

Alcohol Consumption Increases Epigenetic Age Acceleration: A new study has found that higher levels of long-term alcohol consumption are associated with a larger gap between the person’s biological and chronological age, but not in the young.

Tweaking the Growth of Stem Cells for Better Therapies: Researchers publishing in ACS Nano have described how culturing stem cells on nanogratings instead of flat substrates changes the effects of the extracellular vesicles (EVs) they send, potentially paving the way to a new system of therapies.

Lifestyle Interventions Against Cellular Senescence: A new review summarizes our knowledge about lifestyle interventions, such as exercise, healthy diet, and good sleep, that can possibly reduce cellular senescence.

Olive Oil Fights Cognitive Decline in Clinical Trials: In a recent review published in Frontiers in Nutrition, the researchers reviewed studies linking olive oil consumption to cognitive performance.

Cells Regularly Donate Mitochondria to One Another: In a review published in Nature, researchers have explained how and why cells transfer mitochondria to one another, proposing that this transfer allows organisms to be more resilient against energy deficiencies.

Mediterranean, Keto, and Plant-Based Diets Vs. Cancer: A new review summarizes what we know about the Mediterranean, keto, and plant-based diets and their effects on cancer risk and progression.

Targeting Metabolism to Protect Against Stroke: Japanese researchers publishing in Aging have described how improving the AMPK metabolic pathway improves outcomes in a rat model of stroke.

A Phytomolecule Improves Tendon Regeneration in Rats: A new study has identified a molecule found in Saposhnikovia root as a potent mediator of tendon regeneration in rats. The results were also replicated in human cells.

Promoting Health and Longevity Through Diet: A review published in the Journal of Internal Medicine summarized current knowledge on the impact of dietary factors on chronic diseases and longevity.

Senolytics May Work Against Long COVID in the Brain: A new publication in Nature Aging has used organoids and model mice to discover that senolytics may be effective treatments for neurodegeneration caused by the post-infection syndrome known as long COVID.

Plant-Based Alternatives Are Associated With Less Disease: A new meta-analysis has found that in many cases, switching from an animal product to a plant-based alternative is associated with less cardiovascular, diabetes, and all-cause mortality risk

Pushing Forward on Understanding Cellular Decline: Researchers publishing in Nature Aging have investigated one of the core biological reasons behind the decline of stem cells’ ability to proliferate.

A Lack of Skin Collagen May Encourage Cancer Growth: A paper published in Nature has described how the aging extracellular matrix causes physical changs to the skin that make it easier for cancer to grow.

Young People More Vulnerable to Atherosclerosis Risk Factors: One study suggests that increases in LDL cholesterol and systolic blood pressure elevate the risk of atherosclerosis progression more in younger than in older people. The good news is that this can be reversed.

Dual-Purpose Molecular Targets for Cancer and Aging: A study published in Aging Cell applied an artificial intelligence target discovery platform to aid in identifying potential dual-purpose targets for anti-aging and anti-cancer treatments.

Some HIV-Fighting Drugs May Also Fight Aging: Publishing in Ageing Research Reviews, a team of researchers including Vera Gorbunova has described how a class of drugs originally used to treat HIV might be used to affect some of the hallmarks of aging.

Aging Might Blunt the Effects of Fasting: Scientists have found that in killifish, old age is associated with a dampened response to fasting and identified the protein that might be responsible. A similar mechanism might exist in humans.

Predicting a Species’ Longevity Through Epigenetics: A preprint study published on bioRxiv discusses how a species’ maximum lifespan can be predicted by its epigenetics, showing that these differences are largely unaffected by interventions.

Mammals Accumulate Epigenetic Noise With Age: In Nature Communications, researchers have explained how epigenetic drift and disorder are associated with shorter lifespans across species and that some species accumulate this noise considerably faster than others.

Isoleucine Restriction Boosts Lifespan in Mice: A new study reports a massive 33% increase in median lifespan in male genetically heterogeneous mice following prolonged isoleucine restriction.

Music Therapy for Treating Alzheimer’s Disease: The authors of a new review have analyzed randomized controlled trials that evaluated the impact of music therapy on the cognitive functions of people with Alzheimer’s.

Running Is Associated With Better Health Biomarkers: In a recent publication in PLOS One, researchers have described the metabolic effects on running in generally healthy people. A lack of activity is a known risk factor for early mortality.

Implanting mechanically reprogrammed fibroblasts for aged tissue regeneration and wound healing: Transcriptome analysis, combined with chromatin biomarkers, revealed that implanted cells upregulated tissue regeneration and wound healing pathways. These results provide a novel, nongenetic, partial reprogramming of aged cells for cell-based therapies in regenerative medicine.

Sleep regularity and mortality: a prospective analysis in the UK Biobank: Irregular sleep-wake patterns are associated with higher mortality risk, including mortality due to cancer and cardiovascular disease.

Calorie restriction reduces biomarkers of cellular senescence in humans: These results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.

Mechanisms underlying retardation of aging by dietary energy restriction: Overnutrition disrupts FoxO- and Npy-associated metabolic and mitochondrial bioenergetic adaptive processes, causing the acceleration of aging and related diseases.

Effect of Dietary Sodium on Blood Pressure: This crossover trial assesses whether high-sodium and low-sodium dietary interventions affect 24-hour ambulatory blood pressure measures among middle-aged to elderly adults with normotension, controlled hypertension, uncontrolled hypertension, or untreated hypertension.

Dietary Sodium Intake and Risk of Incident Type 2 Diabetes: To fill the knowledge gap of the relation between long-term dietary sodium intake and type 2 diabetes (T2D), the researchers evaluated the association between the frequency of adding salt to foods, a surrogate marker for evaluating the long-term sodium intake, and incident T2D risk.

Effects of exercise interventions on cognitive functions in healthy populations: A systematic review and meta-analysis: Chronic exercise intervention is a non-pharmacological therapy suggested to improve cognitive function in various populations.

Efficacy of morning versus afternoon aerobic exercise training on reducing metabolic syndrome components: High-intensity aerobic exercise training in the morning in comparison to training in the afternoon is somewhat more efficient at reducing cardiometabolic risk factors (i.e. systolic blood pressure and insulin sensitivity).

Dose-response of accelerometer-measured physical activity, step count, and cancer risk in the UK Biobank: a prospective cohort analysis: In this sample from the UK Biobank, higher total physical activity and daily step count were associated with lower risk of physical-activity-related cancers. Findings suggest additional physical activity time, irrespective of intensity, may be beneficial. Increasing low intensity activity time and increasing daily step counts could be practical.

Effect of physical activity on risk of Alzheimer’s disease: A systematic review and meta-analysis of 29 prospective cohort studies: PA intervention reduces the incidence of AD, but merely in moderate to vigorous PA with follow-up of less than 15 years, thus conditionally recommending the popularization of PA as a modifiable lifestyle factor to prevent AD.

Tumor cell-induced macrophage senescence plays a pivotal role in tumor initiation followed by stable growth in immunocompetent condition: This paper reports that tumor growth can be inhibited by externally administered NMN against a macrophage senescence-like state that occurs in the very early stages of tumor-initiating cell development.

Fermented cereal-origin gerobiotic cocktails promote healthy longevity in Caenorhabditis elegans: Several single-strain gerobiotics have proven to be beneficial in alleviating aging and age-related functional declines across species, but multistrain/multispecies gerobiotics appear to be even more useful.

Antibiotics that target mitochondria extend lifespan in C. elegans: Mitochondrial inhibitors (i.e., mitochondria-targeting antibiotics) could abrogate aging and extend lifespan in C. elegans.

A Combination Study of Pre- and Clinical Trial: Seaweed Consumption Reduces Aging-Associated Muscle Loss: This treatment helps maintain muscle mass and delays muscle wasting during aging, suggesting it as a potent nutritional strategy to protect against aging-associated sarcopenia.

Microvesicles-hydrogel breaks the cycle of cellular senescence by improving mitochondrial function to treat osteoarthritis: Through responding to ROS levels, this hydrogel intelligently releases MVs and enhances mitochondrial function in chondrocytes to improving cellular senescence.

In vivo reprogramming leads to premature death linked to hepatic and intestinal failure: In transgenic mice, continuous induction of the reprogramming factors in vivo leads to hepatic and intestinal dysfunction, resulting in decreased body weight and contributing to death within 1?week.

Mid-old cells are a potential target for anti-aging interventions in the elderly: In this study, the authors introduce the concept of a unique cellular subtype within the organic stroma, which does not conform to a typical young or senescent cell.

Electric currents of 448?kHz upregulate anti-senescence pathways in human dermal fibroblasts: CRET treatment improves a number of functions related to migration and proliferation, and it reduces age-related cellular changes in human dermal fibroblasts.

The longevity bottleneck hypothesis: Could dinosaurs have shaped ageing in present-day mammals?: Although mammals, such as humans, can evolve long lifespans, they do so under constraints dating to the dinosaur era.

Survival and longevity of European rulers: geographical influences and exploring potential factors, including the Mediterranean diet: Although the Mediterranean diet is often associated with health benefits, these findings indicate that it alone may not account for differences in ruler longevity across regions.

News Nuggets

Rejuve’s Longevity App Welcomes Peptide Bioregulator: ‘Longevity’, an app designed to empower everyone to live longer, healthier lives, welcomes its latest partner, Peptide Bioregulator, a high-quality supplement company.

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Date Posted: November 30, 2023

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Running Is Associated With Better Health Biomarkers

In a recent publication in PLOS One, researchers have described the metabolic effects on running in generally healthy people.

A lack of activity is a known risk factor

This paper begins with warnings against sedentary behavior, citing one study reporting that it is responsible for approximately 1 out of 12 early deaths in the United States, on par with smoking and obesity [1]. Many studies have reported exercise to be highly effective as a medical intervention, including for such age-related conditions as type 2 diabetes [2].

However, nearly all studies on exercise are either on its effects on people with diagnosed disorders [3] or committed athletes [4], meaning that its effects on the general population are less detailed. Therefore, these researchers have developed a study to fill this gap, with their study using data from generally healthy individuals.

A health platform provides a broad dataset

This study used data gleaned from a total of 23,237 of the InsideTracker platform’s subscribers. The participants volunteered their data to be used for research purposes, which consisted both of blood testing and self-reported information. Notably, while medical history was not part of the platform or this study, the participants had blood biomarkers within normal ranges and did not have any diagnosed chronic conditions.

As expected, because this was a study of people’s normal habits, people who ran regularly were both younger and considerably leaner than people who did not. Regular cardio exercise is very well-known to have effects on body mass, and obesity is known to have effects on metabolic markers. The researchers took this into account, adjusting for age, gender, and body mass index (BMI).

Significant associations with biomarkers

Running was associated with less blood glucose, fewer white blood cells, less of the “bad” cholesterol LDL, and less of the inflammatory biomarker hsCRP. Instead, more frequent runners had more B12, folate, and vitamin D in their systems along with more of the “good” cholesterol HDL. Professional-level runners also had less blood magnesium.

Some of these changes in biomarkers were associated with sex. For example, hematocrit and hemogloblin, two metrics of oxygen carrying capacity, were only significantly associated in males with professional-level running, while these metrics were improved in women with running at all levels.

The association with lower BMI was striking and across-the-board. Among the participants in this study, the majority of the sedentary men were overweight as defined by the CDC (BMI > 25), while women who did not run were also considerably more likely to be overweight. This chart is organized by levels of running, decreasing left to right.

Unsurprisingly, nearly all of the associations between running and health biomarkers could be explained by its relationship with BMI. Inflammation, glucose, and lipid metabolism biomarkers were directly related to this metric. After conducting statistical analyses in an effort to control for BMI, the researchers found that vigorous physical activity was still associated with reduced inflammation and glucose along with more HDL.

Limitations and caveats

This is an association study that cannot prove causality. Most notably, while the researchers were able to adjust for BMI, they acknowledged that they could only predict, rather than measure, running being associated with other healthy habits. For example, levels of crucial vitamins were higher in more serious runners, which is likely to be the result of different dietary practices rather than the running itself. HDL and LDL cholesterol are also known to be affected by diet.

This study relied on self-reported amounts of running, which may not be fully reliable. It also had an inherent bias: the people involved were volunteers who had signed up for a health product, which is not likely to be an accurate cross-section of the general population. Still, this study provides insight into the many positive associations between regular exercise and overall health.

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Literature

[1] Carlson, S. A., Adams, E. K., Yang, Z., & Fulton, J. E. (2018). Peer reviewed: percentage of deaths associated with inadequate physical activity in the United States. Preventing chronic disease, 15.

[2] Sgro, P., Emerenziani, G. P., Antinozzi, C., Sacchetti, M., & Di Luigi, L. (2021). Exercise as a drug for glucose management and prevention in type 2 diabetes mellitus. Current opinion in pharmacology, 59, 95-102.

[3] Lin, X., Zhang, X., Guo, J., Roberts, C. K., McKenzie, S., Wu, W. C., … & Song, Y. (2015). Abstract P270: Effects of Exercise Training on Cardiorespiratory Fitness and Biomarkers of Cardio-metabolic Health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Circulation, 131(suppl_1), AP270-AP270.

[4] Lee, E. C., Fragala, M. S., Kavouras, S. A., Queen, R. M., Pryor, J. L., & Casa, D. J. (2017). Biomarkers in sports and exercise: tracking health, performance, and recovery in athletes. Journal of strength and conditioning research, 31(10), 2920.

Date Posted: November 29, 2023

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Music Therapy for Treating Alzheimer’s Disease

The authors of a new review have analyzed randomized controlled trials that evaluated the impact of music therapy on the cognitive functions of people with Alzheimer’s [1].

Music to Alzheimer’s patients’ ears

Current pharmacology lacks a long-term method of effectively managing Alzheimer’s disease symptoms. Therefore, researchers have been looking into non-pharmacological therapies for treating these symptoms. One of these alternatives is music therapy [2].

The American Music Therapy Association describes music therapy as the use of music interventions in a clinical and evidence-based manner to achieve specific goals, which are tailored to the individual, by a professional who is credentialed and has completed an approved music therapy program.

Research on music therapy has reported positive effects on emotion modulation and social communication. It has also been found to affects some brain networks by inducing plastic changes in those networks [3]. In patients who feel isolated, music therapy can lead to a feeling of connection and socialization. It can also help improve mood, cognitive functions, and memory [4].

There are two approaches to music therapy: active and receptive. Active musical intervention techniques require more engagement, such as improvisation, singing, playing an instrument, clapping, or dancing. On the other hand, the receptive version merely involves listening to music [5].

Previous research on active music interventions has found that they can improve cognitive functions and reduce agitation and anxiety. Meanwhile, the receptive version has been found to aid in relaxation, stress reduction, and sleep quality [3].

Singing seems to have an effect on Alzheimer’s symptoms

The researchers analyzed eight studies that included 689 participants from the USA, Europe, and Asia. The mean ages of participants in those studies were between 60.5 and 87.1, with Alzheimer’s disease stages varying from mild to severe. The musical approaches also varied in those studies and included singing with played songs, listening to music, and other active and passive approaches [6-13].

All but one study concluded that music therapy had a significant, positive impact on Alzheimer’s disease patients’ cognitive function. The positive results reported improvement in orientation, language, memory, verbal fluency, and the emotional state of the patients. The improvements in the emotional state didn’t last longer than 3 weeks after the therapy; other effects lasted longer and were still observed after the follow-up, which varied between 1 month and 6 months.

Further analysis revealed that active therapy had better results than the receptive version. Still, the two studies that only used receptive methods showed positive effects on cognitive functions.

The review’s authors elaborate that the lack of association between cognition and music therapy in one of the analyzed studies might be due to a few reasons. First, in that study, the therapist chose the music used during the therapy, and it was not based on the participant’s preference. Second, the control group was a group of participants who participated in a cooking activity rather than no intervention. Third, there might not have been enough participants to report significant results.

Potential and limitations

The authors list many advantages of employing music therapy in treating symptoms of Alzheimer’s disease, including its easy implementation, affordability, lack of side effects, and non-invasive nature. Additionally, multiple Alzheimer’s Disease symptoms can be addressed simultaneously.

However, the cognitive and physical abilities of patients with severe dementia might prevent them from taking part, thus limiting its implementation to patients with less advanced stages of the disease. Additionally, the trained therapists required for music therapy might not be available everywhere.

The authors also point to some of the limitations of the review. The studies included in the review are quite heterogeneous, as their implementations of music therapy differed in kind and duration. They also measured different outcomes in participants of different ages and with different disease severities..

Those limitations and the small number of studies analyzed don’t allow the authors to offer any recommendations regarding best practices or practical implementation as to which types of interventions or music might be best for Alzheimer’s patients. They concluded as follows:

The findings of this review suggest that music therapy could have a positive impact on cognitive functions in patients with AD. This supports the growing body of evidence that targets music therapy as a promising cognitive rehabilitating process aiming to improve cognitive functions in individuals with AD dementia, like memory, executive functions, or attention. Improvements in these cognitive functions can, in turn, enhance the quality of life of both the patients and their caregivers. However, more research is needed to fully understand the mechanisms behind these effects and to determine the optimal approach to music therapy for this population, including the time frame for follow-up evaluations.

If you found this interesting and want to find out more about the potential of music to treat Alzheimer’s, check out this Stranger Things video we made below.

Can Music Fight a Real Life Vecna? Stranger Things Running Up That Hill Explained - Science Blast

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Literature

[1] Bleibel, M., El Cheikh, A., Sadier, N. S., & Abou-Abbas, L. (2023). The effect of music therapy on cognitive functions in patients with Alzheimer’s disease: a systematic review of randomized controlled trials. Alzheimer’s research & therapy, 15(1), 65.

[2] Särkämö, T., Tervaniemi, M., Laitinen, S., Numminen, A., Kurki, M., Johnson, J. K., & Rantanen, P. (2014). Cognitive, emotional, and social benefits of regular musical activities in early dementia: randomized controlled study. The Gerontologist, 54(4), 634–650.

[3] Schlaug G. (2009). Part VI introduction: listening to and making music facilitates brain recovery processes. Annals of the New York Academy of Sciences, 1169, 372–373.

[4] Raglio, A., Attardo, L., Gontero, G., Rollino, S., Groppo, E., & Granieri, E. (2015). Effects of music and music therapy on mood in neurological patients. World journal of psychiatry, 5(1), 68–78.

[5] Raglio, A., & Oasi, O. (2015). Music and health: what interventions for what results?. Frontiers in psychology, 6, 230.

[6] Sakamoto, M., Ando, H., & Tsutou, A. (2013). Comparing the effects of different individualized music interventions for elderly individuals with severe dementia. International psychogeriatrics, 25(5), 775–784.

[7] Narme, P., Clément, S., Ehrlé, N., Schiaratura, L., Vachez, S., Courtaigne, B., Munsch, F., & Samson, S. (2014). Efficacy of musical interventions in dementia: evidence from a randomized controlled trial. Journal of Alzheimer’s disease : JAD, 38(2), 359–369.

[8] Gómez Gallego, M., & Gómez García, J. (2017). Music therapy and Alzheimer’s disease: Cognitive, psychological, and behavioural effects. Musicoterapia en la enfermedad de Alzheimer: efectos cognitivos, psicológicos y conductuales. Neurologia (Barcelona, Spain), 32(5), 300–308.

[9] Pongan, E., Tillmann, B., Leveque, Y., Trombert, B., Getenet, J. C., Auguste, N., Dauphinot, V., El Haouari, H., Navez, M., Dorey, J. M., Krolak-Salmon, P., Laurent, B., Rouch, I., & LACMé Group (2017). Can Musical or Painting Interventions Improve Chronic Pain, Mood, Quality of Life, and Cognition in Patients with Mild Alzheimer’s Disease? Evidence from a Randomized Controlled Trial. Journal of Alzheimer’s disease : JAD, 60(2), 663–677.

[10] Innes, K. E., Selfe, T. K., Brundage, K., Montgomery, C., Wen, S., Kandati, S., Bowles, H., Khalsa, D. S., & Huysmans, Z. (2018). Effects of Meditation and Music-Listening on Blood Biomarkers of Cellular Aging and Alzheimer’s Disease in Adults with Subjective Cognitive Decline: An Exploratory Randomized Clinical Trial. Journal of Alzheimer’s disease : JAD, 66(3), 947–970.

[11] Lyu, J., Zhang, J., Mu, H., Li, W., Champ, M., Xiong, Q., Gao, T., Xie, L., Jin, W., Yang, W., Cui, M., Gao, M., & Li, M. (2018). The Effects of Music Therapy on Cognition, Psychiatric Symptoms, and Activities of Daily Living in Patients with Alzheimer’s Disease. Journal of Alzheimer’s disease : JAD, 64(4), 1347–1358.

[12] Wang Z, Li Z, Xie J, Wang T, Yu C, An N. (2018) Music therapy improves cognitive function and behavior in patients with moderate Alzheimer’s disease. Int J Clin Exp Med. 2018;11(5):4808–14.

[13] Gómez-Gallego, M., Gómez-Gallego, J. C., Gallego-Mellado, M., & García-García, J. (2021). Comparative Efficacy of Active Group Music Intervention versus Group Music Listening in Alzheimer’s Disease. International journal of environmental research and public health, 18(15), 8067.

Date Posted: November 28, 2023

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Isoleucine Restriction Boosts Lifespan in Mice

A new study reports a massive 33% increase in median lifespan in male genetically heterogeneous mice following prolonged isoleucine restriction [1].

Not all calories are created equal

Caloric restriction is the most powerful life-extending intervention in rodents and primates [2], but the needed magnitude (about 30% fewer calories) is virtually impossible to maintain in humans for long. Yet, the key might not be the number of calories, but their source.

Recent years have seen heated debate about the recommended intake of protein and specific amino acids. On one hand, low protein intake is associated with a major reduction in cancer and overall mortality in people 65 and younger [3]. On the other hand, in older people, high protein intake might be needed to counteract frailty. To complicate things even further, a recent twin study found that higher protein intake is paradoxically associated with sarcopenia [4].

Of all amino acids, methionine has received the most attention. Methionine restriction extends healthspan and lifespan in various animal models [5]. Promising results have also been reported for the three branch-chained amino acids (BCAAs): leucine, isoleucine, and valine [6].

In this new study, a group of researchers who previously reported the health benefits of isoleucine restriction in genetically homogeneous B6 mice applied the same intervention to genetically heterogeneous HET3 mice. This is a step forward, suggesting high generalizability of the results.

More calories, less weight

9-week-old mice were put on either an isoleucine-restricted diet (Low Ile), or a protein-restricted one with lower levels of all amino acids (Low AA). Per weight, all three chows (including the regular one for the control group) had identical caloric density and fat contents. In the Low AA diet, carbohydrates were used to replace calories from amino acids, while in the Low Ile diet, non-essential amino acids replaced calories lost due to isoleucine restriction.

Interestingly, both study groups consumed much more calories than controls. The Low AA group still consumed less amino acids than controls, while the Low Ile group consumed less isoleucine but more total amino acids than the two other groups. Despite getting more calories, body weight in the Low AA group remained on par with that of controls, while the Low Ile group quickly lost weight over the first week of the experiment and stayed lean.

Here, sex differences began to emerge, with female Low Ile mice gaining some weight, although less than female mice in the two other groups.

How did the Low AA and Low Ile groups manage to stay at least as lean as controls despite higher caloric intake? Apparently, by maintaining much higher levels of activity and energy expenditure. Interestingly, Low Ile mice were very similar in their activity levels and caloric intake to Low AA mice, yet they stayed much leaner.

Massive sex-dependent increase in lifespan

To see whether isoleucine restriction could promote healthy aging, the researchers ran a longer experiment, with mice put on different diets at six months of age. The body weight dynamic was largely similar to the first experiment (although all groups lost weight during the second half of life). Importantly, Low Ile mice of both sexes showed better blood glycemic control than Low AA mice or controls.

Most importantly, isoleucine restriction led to a 33% percent increase in median lifespan and to some increase in maximum lifespan in male mice vs controls. This result is one of the most impressive for any intervention ever tested in rodents, especially in HET3 mice. For females, however, the increase in maximum lifespan was only 7%. In the Low AA group, no significant changes vs controls were recorded.

In accordance with the lifespan results, male, but not female, Low Ile mice experienced significantly less frailty than the two other groups. Cancer is the cause of death in more than 80% of HET3 mice. Low Ile males were significantly less likely to get cancer during their lives, but Low Ile females were not. Interestingly, the benefits of isoleucine restriction seemed to be more pronounced in young mice than in older ones. For instance, the considerable gap in fitness observed in young Low Ile mice versus controls all but closed by the age of 28 months. The robust molecular changes caused by the Low Ile diet in young mice also seemed to peter out by then.

“We like to say a calorie is not just a calorie,” says Dudley Lamming, a professor and metabolism researcher at the University of Wisconsin School of Medicine and Public Health, the study’s corresponding author. “Different components of your diet have value and impact beyond their function as a calorie, and we’ve been digging in on one component that many people may be eating too much of.”

While the lifespan results are undoubtedly impressive, many questions remain. For instance, some of the effects of the Low Ile diet may be explained by the abundance of other amino acids in it. This goes against previous research demonstrating some lifespan and healthspan benefits of protein restriction, but some amino acids may have different effects on fitness and lifespan than others.

Foods high in isoleucine include beef, chicken, pork, fish, tofu, dairy, beans, lentils, whole grains, nuts, seeds, and peas. However, it is not yet clear how the study’s findings might apply to humans.

Yes I will donate❤️

Literature

[1] Green, C. L., Trautman, M. E., Chaiyakul, K., Jain, R., Alam, Y. H., Babygirija, R., … & Lamming, D. W. (2023). Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice. Cell Metabolism, 35(11), 1976-1995.

[2] Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., … & Aujard, F. (2018). Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. Communications biology, 1(1), 30.

[3] Levine, M. E., Suarez, J. A., Brandhorst, S., Balasubramanian, P., Cheng, C. W., Madia, F., … & Longo, V. D. (2014). Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell metabolism, 19(3), 407-417.

[4] Ni Lochlainn, M., Bowyer, R. C., Welch, A. A., Whelan, K., & Steves, C. J. (2023). Higher dietary protein intake is associated with sarcopenia in older British twins. Age and Ageing, 52(2), afad018.

[5] Orentreich, N., Matias, J. R., DeFelice, A., & Zimmerman, J. A. (1993). Low methionine ingestion by rats extends life span. The Journal of nutrition, 123(2), 269-274.

[6] Richardson, N. E., Konon, E. N., Schuster, H. S., Mitchell, A. T., Boyle, C., Rodgers, A. C., … & Lamming, D. W. (2021). Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice. Nature Aging, 1(1), 73-86.

Date Posted: November 27, 2023

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Mammals Accumulate Epigenetic Noise With Age

In Nature Communications, researchers have explained how epigenetic drift and disorder are associated with shorter lifespans across species.

When randomness is a problem

We have previously reported on research demonstrating that epigenetic clocks are most likely to be measuring noise. This paper builds on that concept, citing previous research showing that this gradual epigenetic drift is a strong influence on the lifespan of mammals [1] and that it can be broadly used as an epigenetic clock [2].

Epigenetic Alterations

Epigenetic alterations are age-related changes in gene expression that harm the fundamental functions of cells and increase the risk of cancer and other age-related diseases. One of the proposed reasons we age is the changes to gene expression that our cells experience as we get older; these are commonly called epigenetic alterations. These alterations harm the fundamental functions of our cells and can increase the risk of cancer and other age-related diseases.
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Proper DNA methylation, the fundamental biological mechanic behind epigenetics, is part of genomic stability maintenance [3] and is the reason why tissues perform specific functions. The density of methylation sites in certain areas has also been found to be associated with longevity [4], and this relationship may be part of the data used by a recently built tool to predict mammalian lifespan.

This research takes a closer look at this concept, comparing the lifespan of various mammals to the rates at which their epigenomes accumulate drift.

Disorder accumulates in mammals

The researchers began their experiments by first studying the genomes of rats, mice, dogs, and baboons. Interestingly, in samples taken from all four species, some regions became less disordered with time, although considerably more accumulated disorder. As expected, rats and mice, being considerably shorter-lived, were found to accumulate disorder much faster than dogs and baboons, which have similar, longer, lifespans.

However, not all of these species began with the same amount of measured epigenetic disorder. Rats and baboons appeared to share similar amounts at young ages, and mice and dogs shared similar amounts as well, despite their differences in lifespan. Dogs had many considerably denser methylation sites than the other three species, and in dogs and baboons, the relationship between site density and methylation rate was largely flat.

Site density and disorder were also interlinked, particularly in rats and mice. In these short-lived species, disorder accumulated more rapidly in their less-dense sites, and they have fewer dense sites than longer-lived species as well.

In rats, mice, and dogs, the most strongly affected genes were broadly found to be associated with gene transcription regulation and activity along with DNA binding and organismal development. This suggests that this epigenetic noise may be affecting genomic stability over time.

Epigenetic density is not protection

While the density of methylation sites was broadly associated with reduced regional disorder, most strongly in rats and mice, it clearly does not confer substantial protection against accumulating noise: even in their densest regions, rodents accumulated disorder considerably faster than longer-lived species.

Just as longer-lived species have documented protections against genomic instability [5], longer-lived species clearly have epigenetic protections that shorter-lived animals lack. If their mechanisms can be fully identified and explained, it may be possible to transfer them to our pets and, ultimately, to ourselves.

Yes I will donate❤️

Literature

[1] Mendelsohn, A. R., & Larrick, J. W. (2017). Epigenetic drift is a determinant of mammalian lifespan. Rejuvenation research, 20(5), 430-436.

[2] Mayne, B., Berry, O., Davies, C., Farley, J., & Jarman, S. (2019). A genomic predictor of lifespan in vertebrates. Scientific Reports, 9(1), 1-10.

[3] Bird, A. P. (1986). CpG-rich islands and the function of DNA methylation. Nature, 321(6067), 209-213.

[4] McLain, A. T., & Faulk, C. (2018). The evolution of CpG density and lifespan in conserved primate and mammalian promoters. Aging (Albany NY), 10(4), 561.

[5] Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., … & Gorbunova, V. (2019). SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. Cell, 177(3), 622-638.

The Journal Club is a monthly livestream hosted by Dr. Oliver Medvedik which covers the latest aging research papers.

Date Posted: November 27, 2023

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B12 Is a Limiting Factor for Induced Cellular Plasticity

Due to Thanksgiving happening on our usual timeslot, the Journal Club returns on December 1st at 12 Eastern. The show will be livestreamed on the lifespan.io Facebook channel and hosted by Dr. Oliver Medvedik. This month, we will be taking a look at a new paper relating to partial cellular reprogramming and includes Manuel Serrano among the various authors. The open access paper is called Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair.

If you want to learn more about partial cellar reprogramming and the Yamanaka factors that allow cells to be changed into other cell types and even reverse cellular age, check out our topic below.

Yamanaka Factors - Opportunities for Rejuvenation

Drs. Takahashi and Yamanaka showed that they could use Oct4, Sox2, Klf4, and c-Myc (OSKM) to reprogram cells back to pluripotent, embryonic stem cells. While this discovery showed that cellular identity and aging could be reset with just four reprogramming factors, it causes cells to forget their functions and organs. However, exposure to reprogramming factors for just long enough can reverse the age of a cell without erasing its identity. This is the basis of partial cellular reprogramming.

Abstract

Transient reprogramming by the expression of OCT4, SOX2, KLF4 and MYC (OSKM) is a therapeutic strategy for tissue regeneration and rejuvenation, but little is known about its metabolic requirements. Here we show that OSKM reprogramming in mice causes a global depletion of vitamin B12 and molecular hallmarks of methionine starvation. Supplementation with vitamin B12 increases the efficiency of reprogramming both in mice and in cultured cells, the latter indicating a cell-intrinsic effect. We show that the epigenetic mark H3K36me3, which prevents illegitimate initiation of transcription outside promoters (cryptic transcription), is sensitive to vitamin B12 levels, providing evidence for a link between B12 levels, H3K36 methylation, transcriptional fidelity and efficient reprogramming. Vitamin B12 supplementation also accelerates tissue repair in a model of ulcerative colitis. We conclude that vitamin B12, through its key role in one-carbon metabolism and epigenetic dynamics, improves the efficiency of in vivo reprogramming and tissue repair.

Literature

Kovatcheva, M., Melendez, E., Chondronasiou, D., Pietrocola, F., Bernad, R., Caballe, A., … & Serrano, M. (2023). Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair. Nature Metabolism, 1-20.

Date Posted: November 27, 2023

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Journal Club Nov – B12 and Cell Plasticity

Due to Thanksgiving happening on our usual timeslot, the Journal Club returns on December 1st at 12 Eastern. The show will be livestreamed on the lifespan.io Facebook channel and hosted by Dr. Oliver Medvedik. This month we will be taking a look at a new paper relating to partial cellular reprogramming and includes Manuel Serrano among the various authors. The open access paper is called Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair.

If you want to learn more about partial cellar reprogramming and the Yamanaka factors that allow cells to be changed into other cell types and even reverse cellular age, check out our topic below.

Yamanaka Factors - Opportunities for Rejuvenation

Abstract

Join us on the livestream

As a Lifespan Hero you can join us live on the show using the info below: Join Zoom Meeting Meeting ID: 843 3262 4735 Passcode: 410412

Literature

Date Posted: November 26, 2023

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Predicting a Species’ Longevity Through Epigenetics

A preprint study published on bioRxiv discusses how a species’ maximum lifespan can be predicted by its epigenetics, showing that these differences are largely unaffected by interventions.

Differences and similarities in mammals

The researchers begin their paper with a note that bowhead whales live over a hundred times as long as shrews, even though these are both mammalian species. The reasons behind this have been previously investigated by expert researchers [1]. Various studies have focused on various aspects of aging, including telomeres [2], genomic stability [3], and epigenetics [4], but these researchers note that epigenetic studies have generally suffered from small sample sizes with inconsistent data gathering.

To solve this problem, this study was built using the Mammalian Methylation Consortium, which uses epigenetics from 348 mammalian species in order to determine why some species live much longer than others [5]. This database focuses on 36,000 separate epigenetic sites that are surrounded by similar base pairs across mammals.

A robust dataset, with caveats

Before using this dataset to work on aging, they tested its capability for simple identification. The species of an animal, its sex, and the tissue it came from were nearly universally correctly identified solely through epigenetics, with the sole exception being marmosets, which can transfer cells to each other before birth.

The researchers then put their data to work. Averaging out sex and tissue types, they mapped the epigenetic differences in these species to gestation time, age at sexual maturity, and lifespan. Even when some animals were randomly excluded to test robustness, this model was able to accurately predict these three qualities.

The data remained accurate even when data from very young animals was used. It is possible to take any young mammal, analyze its epigenetics, and have an fairly accurate estimate of how long it will naturally live. This epigenetic correlation was stronger than body weight and the lifespans of related mammalian orders.

Tissue type was found to play a strong role in the model’s estimates. While the average tissue was accurate, certain tissues, such as the blood and outer skin, give inaccurately long estimates. Meanwhile, samples taken from stem cells usually give inaccurately short ones. The researchers built further models to mitigate these confounding factors and create more accurate estimates on a per-tissue basis.

Some things were unpredicted

This model did not predict cancer: no correlation was found between these epigenetic markers of lfiespan and cancer-related mortality risk. While there was an epigenetic influence of high-fat diets, there was little evidence for the influence of caloric restriction. While full epigenetic reprogramming had a small but significant effect, partial reprogramming was not found to have any significant effect on this model’s predictions.

Most critically, these predictions were completely unaffected by factors known to affect lifespan. Taking epigenetic data from the Framingham Heart Study, these researchers found that diet, smoking, fat, and physical abilities had no significant effect on their predictor. Their predictor was even unaffected by dog breeds, even though some dog breeds live considerably longer than others.

The researchers believe that their predictive model is utilizing very basic longevity-related factors that go deeper than the modest changes brought about by lifestyle interventions. They hypothesize that their work could potentially be used to develop substantially stronger interventions that “affect epigenetic maximum lifespan as they may be the key to achieving large lifespan differences observed between species.”

Yes I will donate❤️

Literature

[1] Magalhães, J. P. D., Costa, J., & Church, G. M. (2007). An analysis of the relationship between metabolism, developmental schedules, and longevity using phylogenetic independent contrasts. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 62(2), 149-160.

[2] Gorbunova, V., & Seluanov, A. (2009). Coevolution of telomerase activity and body mass in mammals: from mice to beavers. Mechanisms of ageing and development, 130(1-2), 3-9.

[3] Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., … & Gorbunova, V. (2019). SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. Cell, 177(3), 622-638.

[4] Sen, P., Shah, P. P., Nativio, R., & Berger, S. L. (2016). Epigenetic mechanisms of longevity and aging. Cell, 166(4), 822-839.

[5] Arneson, A., Haghani, A., Thompson, M. J., Pellegrini, M., Kwon, S. B., Vu, H., … & Horvath, S. (2022). A mammalian methylation array for profiling methylation levels at conserved sequences. Nature communications, 13(1), 783.

Date Posted: November 24, 2023

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Aging Might Blunt the Effects of Fasting

Scientists have found that in killifish, old age is associated with a dampened response to fasting and identified the protein that might be responsible. A similar mechanism might exist in humans [1].

Fast less furious

Various fasting regimens are thought to confer health and longevity benefits [2], and some potentially geroprotective drugs actually mimic caloric restriction. However, recent research suggests that the response to fasting might be blunted by old age [3], limiting the potential effect of dietary interventions.

In this new study published in Nature Aging, the researchers used turquoise killifish, a popular fast-aging animal model, to investigate age-related changes in response to fasting and refeeding. Following a five-day fast, a transcriptomic analysis revealed almost 2,500 differentially expressed genes (DEGs) in the visceral adipose tissue of young fish. Just like in mammals, fasting negatively affected many genes related to energy expenditure, protein synthesis, and cellular proliferation. However, in older fish, the transcriptomic effect of fasting was much more modest: only 359 DEGs.

Further analysis found that the reason was not a blunted response to fasting, as the researchers initially assumed. Rather, old animals had a more fasting-like transcriptomic profile by default, and subsequent fasting could only nudge it further a bit. For instance, fasting leads to the release of non-esterified fatty acids (NEFAs) as an alternative energy source. However, both fed and fasted older killifish had elevated NEFA levels.

Aging that looks like fasting

Aging is known to affect feeding behavior. In humans, with age, the recommended caloric intake decreases slightly. The fish in this experiment also ate less as they aged but without showing signs of starvation. Post-meal glucose levels were comparable between young and old fed fish.

Further transcriptional analysis showed more similarity between fasting and aging: 23% of genes changed by those two conditions overlapped, and 92% of such genes changed in the same direction. According to the researchers, one outcome of those genetic changes was decreased energy and lipid metabolism.

Among notable proteins whose levels were altered by fasting and aging was AMPK, a fuel-sensing enzyme central to energy metabolism that often pops up on geroscientists’ radar. In young animals, fasting induced upregulation of one AMPK subunit, γ1, and downregulation of another, γ2, but in older animals, this did not happen.

A bump in lifespan

The researchers introduced a mutation that leads to γ1 activation. Old fish carrying this mutation exhibited a much more pronounced transcriptional response to fasting with little resemblance to age-related transcriptional changes. “Sustained AMPKγ1 complex activation counters the age-associated FLTP (fasting-like transcriptional profile) and maintains energy and lipid metabolism responsiveness to feeding late in life,” the researchers commented.

Increased energy metabolism observed in the mutated fish led to improved tissue homeostasis. Aged mutated animals showed notable upregulation of genes related to DNA repair and cellular proliferation. Inflammatory pathways were among the downregulated, as were genes related to obesity, insulin resistance, and type 2 diabetes. The fish also showed reduced fasting blood glucose and triglycerides along with less age-related visceral adiposity. Most importantly, the mutation increased the fish’s lifespan by 20%.

Not just fish

How relevant is this discovery for humans? The researchers cite an earlier study in which fasting resulted in a similar dynamic in AMPK subunits, although that finding did not reach statistical significance [4]. Using a human gene dataset, the researchers found a significant age-related decrease in PRKAG1, the gene that codes for the AMPKγ1 subunit, in several tissues. Finally, the researchers obtained blood samples from 93 donors aged 65-90 with a broad range of age-related diseases and functional levels. The values of the multidimensional prognostic index (MPI), a measurement of general health, were negatively correlated with PRKAG1 expression, suggesting reduced multimorbidity and improved functional skills in people with higher levels of the protein.

The fasting–refeeding cycle triggers an inverse oscillatory expression of genes encoding the AMP-activated protein kinase (AMPK) regulatory subunits Prkag1 (γ1) and Prkag2 (γ2) in young individuals. Aging blunts such regulation, resulting in reduced Prkag1 expression. Transgenic fish with sustained AMPKγ1 countered the fasting-like transcriptional program, exhibiting a more youthful feeding and fasting response in older age, improved metabolic health and longevity. Accordingly, Prkag1 expression declines with age in human tissues and is associated with multimorbidity and multidimensional frailty risk. Thus, selective activation of AMPKγ1 prevents metabolic quiescence and preserves healthy aging in vertebrates, offering potential avenues for intervention.

Yes I will donate❤️

Literature

[1] Ripa, R., Ballhysa, E., Steiner, J. D., Laboy, R., Annibal, A., Hochhard, N., … & Antebi, A. (2023). Refeeding-associated AMPK?1 complex activity is a hallmark of health and longevity. Nature Aging, 1-17.

[2] Anton, S. D., Moehl, K., Donahoo, W. T., Marosi, K., Lee, S. A., Mainous III, A. G., … & Mattson, M. P. (2018). Flipping the metabolic switch: understanding and applying the health benefits of fasting. Obesity, 26(2), 254-268.

[3] Hahn, O., Drews, L. F., Nguyen, A., Tatsuta, T., Gkioni, L., Hendrich, O., … & Partridge, L. (2019). A nutritional memory effect counteracts the benefits of dietary restriction in old mice. Nature metabolism, 1(11), 1059-1073.

[4] Defour, M., Michielsen, C. C., O’donovan, S. D., Afman, L. A., & Kersten, S. (2020). Transcriptomic signature of fasting in human adipose tissue. Physiological genomics, 52(10), 451-467.

Date Posted: November 23, 2023

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Some HIV-Fighting Drugs May Also Fight Aging

Publishing in Ageing Research Reviews, a team of researchers including Vera Gorbunova has described how a class of drugs originally used to treat HIV might be used to affect some of the hallmarks of aging.

Inhibiting DNA changes

DNA transcription, which transfers DNA code into the RNA that cells use to make proteins, can also happen in reverse: RNA can be employed to write DNA in reverse transcription. Nucleoside reverse transcriptase inhibitors (NRTIs) are structurally very similar to the four well-known base nucleotides, A, C, G, and T, that make up DNA code. However, once a reverse transcriptase incorporates an NRTI instead of a real nucleotide, it can no longer continue.

NRTIs have been used in the treatment of HIV, which uses reverse transcription to spread [1]. Other research has found that NRTIs reduce inflammation in model mice that do not produce SIRT6 [2], help to fight a class of inflammatory diseases [3], and increase the lifespan of C.elegans worms [4].

Genomic instability and inflammaging

Genomic Instability

Genomic instability is the result of gradual damage to DNA in ways that are not naturally repaired. This is a root cause of aging, and it leads to genetic mutations and an increased risk of cancer.
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LINE1 retrotransposons are introduced into the genome through reverse transcription. Because inserting them requires breaking DNA, these L1 elements have been linked to genomic instability [5]. By blocking the reverse transcription that allows them to spread, NRTIs directly inhibit this process.

L1 elements also become active with cellular senescence and aging, causing cellular inflammation [6]. Therefore, it is unsurprising that NRTIs have been also been reported to fight the age-related increase in inflammation known as inflammaging, and some of the particular pathways that they inhibit have been elucidated [3].

This line of inquiry has resulted in several studies that focus on NRTIs’ anti-inflammatory activity, examining their effects on such diseases as macular degeneration. There are even ongoing human clinical trials that are testing the NRTIs emtricitabine and lamivudie against Alzheimer’s disease.

Inhibiting reverse transcription also upregulates ATF-4, which is related to the natural stress response of cells. This is the driving factor behind its effects in C.elegans worms [4], and other lifespan extension treatments, such as rapamycin and caloric restriction, also upregulate ATF-4 [7].

Side effects

Unfortunately, despite these studies showing promise, this interference with biology can come with potentially deadly side effects. NRTIs are an old class of drugs, and many of the initial efforts, such as the original anti-HIV drug AZT, have since been removed from the market or never placed on it. Newer NRTIs, including lamivudine, are not as dangerous but still have severe side effects, such as liver disease and lactic acidosis.

Many of these side effects can be traced back to NRTIs’ effects on mitochondrial DNA, causing mitochondrial dysfunction: another hallmark of aging. In fact, these mitochondrial effects appear to be a key part of the ATF-4 stress response that increases longevity in some animals. Beneficial amounts of stress response are known as hormesis, and this effect has been reported to improve overall health [8].

With both their benefits and side effects in mind, any effort to use NRTIs for anti-aging purposes must first make sure that these drugs are not doing more harm than good. Further work and testing must be done to determine if any treatment that inhibits reverse transcription can improve health and lifespan rather than reducing it.

Yes I will donate❤️

Literature

[1] Pau, A. K., & George, J. M. (2014). Antiretroviral therapy: current drugs. Infectious Disease Clinics, 28(3), 371-402.

[2] Simon, M., Van Meter, M., Ablaeva, J., Ke, Z., Gonzalez, R. S., Taguchi, T., … & Gorbunova, V. (2019). LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell metabolism, 29(4), 871-885.

[3] Fowler, B. J., Gelfand, B. D., Kim, Y., Kerur, N., Tarallo, V., Hirano, Y., … & Ambati, J. (2014). Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science, 346(6212), 1000-1003.

[4] McIntyre, R. L., Molenaars, M., Schomakers, B. V., Gao, A. W., Kamble, R., Jongejan, A., … & Janssens, G. E. (2023). Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4. Cell reports, 42(1)

[5] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell.

[6] De Cecco, M., Ito, T., Petrashen, A. P., Elias, A. E., Skvir, N. J., Criscione, S. W., … & Sedivy, J. M. (2019). L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature, 566(7742), 73-78.

[7] Li, W., Li, X., & Miller, R. A. (2014). ATF 4 activity: a common feature shared by many kinds of slow-aging mice. Aging cell, 13(6), 1012-1018.

[8] López-Otín, C., & Kroemer, G. (2021). Hallmarks of health. Cell, 184(1), 33-63.

Date Posted: November 22, 2023

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Dual-Purpose Molecular Targets for Cancer and Aging

A new study published in Aging Cell applied an artificial intelligence target discovery platform to aid in identifying potential dual-purpose targets for anti-aging and anti-cancer treatments [1].

Killing two birds with one stone

Aging, as is the case with many diseases, is a risk factor for cancer, and the processes behind aging and cancer are interconnected. Therefore, targeting their common molecular pathways may be effective against both conditions. This interconnection has been described in the literature: for example, some Hallmarks of Aging, which describe common age-related problems, are also frequently associated with cancer [2, 3].

Additionally, some gerotherapeutic drugs, which aim to decrease the burden of age-related diseases, are already FDA approved for cancer treatment [4, 5].

Therefore, the authors of the paper decided to build on that knowledge and “identify potential dual-purpose targets that could delay aging and increase lifespan among healthy individuals as well as inhibit cancer using a list of common cancer targets.”

The quest to find the dual-purpose targets

The researchers used gene expression data from 47 healthy tissues of 980 individuals to identify age-associated genes. They analyzed the differential expression between old and young people in order to build correlations between gene expressions and aging.

For cancer-associated genes, they “used 139 datasets (131 transcriptomics and 8 proteomics) consisting of 11,303 cases and 4431 control samples selected from 11 age-associated solid cancers.”

It would be a Herculean effort to manually review all the datasets containing thousands of genes and proteins, along with their interaction data, in order to identify common cancer and aging targets. Therefore, the researchers employed AI tools, specifically PandaOmics, an AI-driven target discovery engine that they previously developed [6].

The researchers started their work by identifying druggable cancer targets. First, they focused on high-confidence targets that had been broadly discussed in the literature. Second, they looked for novel targets, which had fewer studies or were not well described in scientific literature.

The identified targets were further analyzed regarding age-related expression. In this way, the researchers identified 180 age-associated cancer targets, of which 119 were already associated with FDA-approved or clinical investigational drugs.

The researchers then searched multiple databases to identify which of the 180 age-associated cancer targets could also be potential anti-aging targets, separating them into four groups.

Group 1 consisted of targets described in the literature to have lifespan-extending properties. They were also characterized by the “same direction of therapeutic inhibition or activation for anti-aging and anti-cancer treatment.” Group 2 also consisted of targets described in the literature to be related to extended lifespans, but inhibiting or activating them for anti-aging would have potentially carcinogenic side effects. Group 3 consisted of targets that shorten lifespan, and Group 4 consisted of cancer targets that weren’t researched regarding lifespan extension

Analysis of the genes included in Group 1 revealed that the genes were likely to be involved in such processes as cellular senescence or other signaling pathways. The researchers also looked at such things as mechanisms of action, clinical trial status, relation to the hallmarks of aging, and role in modulating longevity, and used this information to propose therapeutic approaches. They noted that there already exist FDA-approved inhibitors for three of the targets they identified in Group 1, and five other targets are currently being investigated in clinical trials.

The researchers took a closer look at Group 4, which consisted of potential targets that haven’t yet been investigated in lifespan studies. The researchers performed an analysis comparing the enrichment of biological processes between Group 4 and Groups 1 and 2.

Combining this analysis with an eye towards mechanisms of action and roles in age-associated diseases, the researchers selected 23 potential dual-purpose targets. Just as in the case of the previous group, they proposed therapeutic approaches using those targets. The majority of the identified targets were associated with FDA-approved or investigational drugs.

One of the 23 predicted dual-purpose candidates, lysine-specific demethylase 1A (KDM1A) is involved in carcinogenesis [7], and its inhibitors are currently being tested experimentally [8, 9]. It was also dysregulated during aging in most tissues analyzed in this study. This prompted the researchers to analyze its effect on lifespan.

When a homolog of KDM1A was inactivated in C. elegans worms, it significantly increased the animals’ median lifespan by 15.8%, making it an interesting candidate for further testing as a dual-purpose target.

One drug, two targets

The authors of this study observed that cellular senescence-associated pathways were the most upregulated pathways in both aging and cancer tissues, suggesting that targeting those pathways might combat cancer and delay aging. In this light, the authors speculated about the role of senolytics in the dual-target strategy that they are proposing.

Senolytics have been shown previously to reduce senescence and have a positive impact on age-associated conditions [10]. Since senescence has been shown to promote processes associated with tumor growth [11], these observations suggest that senolytics can be promising candidates, which, through their impact on senescent cells, can lead to delayed aging and cancer treatment.

Senolytics and other molecules that target these identified genes would need to be further tested as potential dual-purpose molecules for treating cancer and aging.

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Literature

[1] Pun, F. W., Leung, G. H. D., Leung, H. W., Rice, J., Schmauck-Medina, T., Lautrup, S., Long, X., Liu, B. H. M., Wong, C. W., Ozerov, I. V., Aliper, A., Ren, F., Rosenberg, A. J., Agrawal, N., Izumchenko, E., Fang, E. F., & Zhavoronkov, A. (2023). A comprehensive AI-driven analysis of large-scale omic datasets reveals novel dual-purpose targets for the treatment of cancer and aging. Aging cell, e14017. Advance online publication.

[2] Aunan, J. R., Cho, W. C., & Soreide, K. (2017). The biology of aging and cancer: A brief overview of shared and divergent molecular hallmarks. Aging and Disease, 8(5), 628–642.

[3] Blagosklonny, M. V. (2022). Hallmarks of cancer and hallmarks of aging. Aging (Albany NY), 14(9), 4176–4187.

[4] Ballou, L. M., & Lin, R. Z. (2008). Rapamycin and mTOR kinase inhibitors. Journal of Chemical Biology, 1(1–4), 27–36. https://doi.org/10.1007/s12154-008-0003-5

[5] Populo, H., Lopes, J. M., & Soares, P. (2012). The mTOR signalling pathway in human cancer. International Journal of Molecular Sciences, 13(2), 1886–1918.

[6] Pun, F. W., Ozerov, I. V., & Zhavoronkov, A. (2023). AI-powered therapeutic target discovery. Trends in Pharmacological Sciences, 44(9), 561–572.

[7] Li, L., Wang, Y., Mou, Y., Wu, H., & Qin, Y. (2021). KDM1A identified as a potential oncogenic driver and prognostic biomarker via multi-omics analysis. Canadian Journal of Infectious Diseases and Medical Microbiology, 2021, 4668565.

[8] Fang, Y., Liao, G., & Yu, B. (2019). LSD1/KDM1A inhibitors in clinical trials: Advances and prospects. Journal of Hematology & Oncology, 12(1), 129.

[9] Karakaidos, P., Verigos, J., & Magklara, A. (2019). LSD1/KDM1A, a gatekeeper of cancer Stemness and a promising therapeutic target. Cancers (Basel), 11(12), 1821.

[10] Raffaele, M., & Vinciguerra, M. (2022). The costs and benefits of senotherapeutics for human health. Lancet Healthy Longev, 3(1), e67– e77.

[11] Collado, M., Blasco, M. A., & Serrano, M. (2007). Cellular senescence in cancer and aging. Cell, 130(2), 223–233.

Date Posted: November 21, 2023

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Young People More Vulnerable to Atherosclerosis Risk Factors

A new study suggests that increases in LDL cholesterol and systolic blood pressure elevate the risk of atherosclerosis progression more in younger than in older people. The good news is that this can be reversed [1].

Creeping atherosclerosis

Atherosclerosis is a major risk factor for cardiovascular disease [2], the primary cause of death in the developed world. Modern medicine has developed techniques to bypass blocked arteries, and drugs, such as statins, that lower the levels of “bad” LDL cholesterol can decrease cardiovascular disease incidence. However, there is a growing understanding that not nearly enough attention is given to preventing atherosclerosis in the first place, including by lifestyle interventions.

This new paper is based on the unique Progression of Early Subclinical Atherosclerosis (PESA) study, a collaboration between the Spanish Centro Nacional de Investigaciones Cardiovasculares (CNIC) and the Santander bank. Back in 2009, more than 4000 healthy middle-aged Santander employees in Madrid volunteered to provide blood samples and undergo noninvasive analysis of the carotid, femoral, and coronary arteries and the aorta. “The PESA study has already made important contributions to our understanding of cardiovascular disease and is considered the most advanced study of its kind in the field,” said Dr. Valentín Fuster, CNIC General Director and Physician-in-Chief at Mount Sinai Medical Center in New York.

Subclinical atherosclerosis is the long asymptomatic phase of the disease that, today, mostly flies under doctors’ radar. According to the study’s authors, it can progress even if LDL cholesterol levels and blood pressure are only slightly elevated.

The youngest are the most vulnerable

At baseline, the participants had a median age of 45 years, and the median follow-up time was 6 years. 44% were diagnosed with subclinical atherosclerosis, an alarming number that illustrates just how widespread this clandestine disease is. By the end of the follow-up period, the incidence increased to 58%.

Most participants remained stable during the follow-up, but 33% experienced worsening of their atherosclerosis clinical pictures; this does not necessarily mean that they went from undiagnosed to diagnosed. Importantly, a small but not insignificant number of people (123) had regression of atherosclerosis.

Progression of the disease was most strongly associated with smoking, LDL cholesterol levels, systolic blood pressure, and the participant being male. Conversely, the strongest predictors for regression were being a nonsmoker, female sex, and lower levels of fibrinogen, an inflammatory protein that has been reported to be a strong risk factor for cardiovascular disease [3]. These were followed by younger age and lower LDL cholesterol.

However, arguably the most interesting finding concerned age. The odds of atherosclerosis progression were more strongly associated with increases in LDL cholesterol and blood pressure in the youngest part of the cohort. With every 10 mg/dL increase in baseline LDL-C, the increase in atherosclerosis progression risk was 9% in participants aged 40-43 years, 6.5% for 44- to 47-year-olds, and 2.5% for people aged 48 and up. Similarly, for every 10 mmHg increase in baseline systolic blood pressure, odds of atherosclerosis progression grew by 27.5%, 10.4%, and 4.8% for those three age groups, respectively.

The case for earlier prevention

As the authors note, it appears that at a younger age, arteries are actually more vulnerable to pathological changes that eventually lead to atherosclerosis. Commenting on the study’s results, Dr. Fuster said that “screening for subclinical atherosclerosis from an early age together with aggressive risk-factor control could help to reduce the global burden of cardiovascular disease.” This is an ‘I told you so’ moment for geroscience, which advocates for early diagnosis and mitigation of age-related pathologies.

According to cardiologist Guiomar Mendieta, the first author of the study, “the other key finding of this study is that atherosclerosis, previously believed to be irreversible, can disappear if risk factors are controlled from an early stage.” However, more research is needed to identify the factors that causally lead to atherosclerosis regression. Several studies have pointed to the possibility of atherosclerosis regression following long-term lifestyle interventions [4].

Over 6 years, subclinical atherosclerosis progressed in one-third of middle-age asymptomatic subjects. Atherosclerosis regression is possible in early stages of the disease. The impact of LDL-C and SBP on subclinical atherosclerosis progression was more pronounced in younger participants, a finding suggesting that the prevention of atherosclerosis and its progression could be enhanced by tighter risk factor control at younger ages, with a likely long-term impact on reducing the risk of clinical events.

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Literature

[1] Mendieta, G, Pocock, S, Mass, V. et al. (2023). Determinants of Progression and Regression of Subclinical Atherosclerosis Over 6 Years. J Am Coll Cardiol., 82 (22) 2069–2083.

[2] Frostegård, J. (2013). Immunity, atherosclerosis and cardiovascular disease. BMC medicine, 11(1), 1-13.

[3] Montalescot, G., Collet, J. P., Choussat, R., & Thomas, D. (1998). Fibrinogen as a risk factor for coronary heart disease. European heart journal, 19, H11-7.

[4] Ornish, D., Scherwitz, L. W., Billings, J. H., Gould, K. L., Merritt, T. A., Sparler, S., … & Brand, R. J. (1998). Intensive lifestyle changes for reversal of coronary heart disease. Jama, 280(23), 2001-2007.

Date Posted: November 20, 2023

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Skin Collagen Loss Makes It Easier For Cancer To Grow

A new paper published in Nature has described how the aging extracellular matrix makes it easier for cancer to grow.

When cancer is skin deep

Under normal circumstances, we lose and regain skin cells constantly. Old skin flakes away, and stem cells constantly divide and differentiate to replace it. This is a homeostatic balance, and a disruption of this balance has been previously reported to lead to cancer, among other problems [1].

Basal cell carcinoma (BCC), the most common form of cancer in people, is caused by known mutations. Specifically, a loss of function of the Patched1 gene or a gain of function of the Smoothed gene leads to an activation of the Hedgehog pathway, leading to cancer [2]. Researchers have replicated this in mice through the mutant cancer-causing gene (oncogene) SmoM2 [3].

However, the skin is dividing constantly, and even oncogenes aren’t always enough to cause tumors to form. The cancer cells don’t always outcompete their normal counterparts, so some skin can look perfectly normal despite some of the cells being cancerous [4]. Therefore, these researchers looked for reasons why oncogenic cells outcompete normal cells, focusing on the cells’ environment.

One place but not another

In mice, SmoM2 cells form tumors in the tails and ears of mice, but not their backs [3]. To investigate this more closely, the researchers developed a mouse model in which Smo2 expression, along with a color change under fluorescent light, is instigated by tamoxifen. This let them visually observe the growth, or lack thereof, of this cancer under different conditions.

Just like in previous research [5], the SmoM2 cells in the ear were able to self-renew and divide rapidly, first expanding to the sides and then invading other skin layers. In the back, the vertical expansion was considerably diminished, but the horizontal expansion was greater. The stress of the cancer’s growth affected the shape of the normal cells in the ear but not the back. The SmoM2 cells in the back also induced terminal differentiation in the normal cells, a sign that they were being outcompeted.

The cancerous cells in the two areas also showed different levels of gene expression. In the ear, the researchers observed a substantial amount of gene upregulation that dovetails with BCC formation, including an increase in the Hedgehog protein and changes in extracellular matrix-related proteins, but these changes in gene expression did not exist in the back. Similarly, increased inflammation was found only in the ear after SmoM2 cells were introduced. The cancer cells were growing and proliferating, but they were not behaving like cancer.

A question of collagen

The researchers noted only a few proteins that were more abundant in the back than the skin tissue. Two of them were related to collagen formation. Collagen is considerably thicker in the backs than the ears of mice, and their skin is substantially thicker. The researchers surmise that this stiffness is the reason why the cancer cells are unable to form tumors.

These results were bolstered by more in-depth studies. The ear tissue of mice varies in thickness, and SmoM2 was less able to invade the more collagen-dense regions. Similarly, and critically, mice older than 18 months begin to lose collagen thickness in the same way as elderly humans. As expected, SmoM2 cells readily formed BCC in the backs of aged mice. Exposure to ultraviolet radiation, which depletes collagen, was found to have similar effects.

While this was not a human study, and human carcinomas may not always behave the same way as in mice, the researchers note that BCC increases with age in people as well. Further research will need to be done to determine how much collagen thickness affects the growth of this cancer and if collagen-improving treatments can help to prevent it.

Yes I will donate❤️

Literature

[1] Blanpain, C., & Simons, B. D. (2013). Unravelling stem cell dynamics by lineage tracing. Nature reviews Molecular cell biology, 14(8), 489-502.

[2] Epstein, E. H. (2008). Basal cell carcinomas: attack of the hedgehog. Nature Reviews Cancer, 8(10), 743-754.

[3] Youssef, K. K., Van Keymeulen, A., Lapouge, G., Beck, B., Michaux, C., Achouri, Y., … & Blanpain, C. (2010). Identification of the cell lineage at the origin of basal cell carcinoma. Nature cell biology, 12(3), 299-305.

[4] Kakiuchi, N., & Ogawa, S. (2021). Clonal expansion in non-cancer tissues. Nature Reviews Cancer, 21(4), 239-256.

[5] Sánchez-Danés, A., Hannezo, E., Larsimont, J. C., Liagre, M., Youssef, K. K., Simons, B. D., & Blanpain, C. (2016). Defining the clonal dynamics leading to mouse skin tumour initiation. Nature, 536(7616), 298-303.

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