$25 million sale of ChromaDex stock | Lifespan Research Institute

Date Posted: February 24, 2021

ChromaDex $25 Million Sale of Common Stock

ChromaDex has recently announced that it has agreed a securities purchase agreement for the sale of $25 million of its common stock in a private placement. The private placement was led by an international investor, with ChromaDex agreeing to sell 3,846,153 shares of its common stock at a per-share price of $6.50.

ChromaDex is the manufacturer of the popular supplement nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+) and a major regulator of energy metabolism. ChromaDex sells its NR via the brand name Tru Niagen.

Nicotinamide Adenine Dinucleotide (NAD): Benefits and Research

Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. It is a dinucleotide, which means that it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base, and the other contains nicotinamide.
Read More

ChromaDex has proven popular with biohackers

The company has become well known in biohacking and supplement enthusiast circles and has even attracted the attention of actress and fitness guru Brooke Burke, who some readers may know from Dancing with the Stars, which she initially won and then went on to co-host. Interestingly, Brooke Burke is also a self-confessed biohacking geek and is interested in the rising trend of wellness, which includes dietary supplements, fitness, and healthy aging.

Melissa Meyers, Creative Director of the lifestyle blog The Glow Girl, is another popular personality who has been enthusiastic about NR. She is one of a growing number of influencers who embrace aging and give advice on how to age gracefully, or as we like to think of it, how to best cope with the fact we are all slowly falling apart.

Of course, our field has far more ambitious ideas about what to do about aging, but it is good that at least an increasing number of people are getting around to the idea that there are things that they can do to potentially slow aging down. This is not necessarily a bad thing while we wait, as better things are developed that could potentially reverse aging on a cellular level.

It’s likely that we are really not that far away from seeing the first human therapies that target aging; we discuss some of these near-future technologies, drugs, and companies in Looking Forward to a Productive 2021 in Aging Research.

The future of ChromaDex

“With this additional capital, we intend to further our position as the world’s leading NAD+ company with expanded scientific research on nicotinamide riboside (NR) and other NAD+ precursors,” says ChromaDex CEO Rob Fried in his company’s press release. “We will also expand our marketing efforts on our flagship consumer brand, Tru Niagen, the safest and most efficient way to boost NAD+ levels, while continuing to protect our intellectual property against infringers.”

The last part is surely a reference to the legal battle that ChromaDex has been having with rival NR company Elysium. Originally, Elysium was supplied by ChromaDex and used its NR in Basis, one of Elysium’s products; however, the supply arrangement was ended and their relationship unraveled, ultimately descending into legal battles.

In 2018, ChromaDex filed a suit against Elysium for infringement of its NR patent, and this is almost certainly what the last part of its press release statement is referring to. The suit is slated to go to court in September 2021, and we will be following the outcome of that case closely to see if ChromaDex can retain the sole right to manufacture and supply NR.

Legal battles aside, we hope that the future development for NR will include more clinical trials and testing of the supplement, including fair comparative studies alongside other NAD+ precursors.

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Date Posted: February 24, 2021

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Longevity Pharmacology has Come of Age

A bold feature article published in Drug Discovery Today illustrates the coming of age of longevity pharmacology.

Dr. João Pedro de Magalhães, one of the biggest names in longevity research, outlined some of the great strides taken in the last two decades, as various discoveries have been made in the biology of aging. Lifespan has been manipulated in model organisms via genetic, dietary, behavioral, and, most recently, pharmacological interventions. The potential commercial and societal value is truly astronomical if these findings can be successfully translated into humans, and evidence is building that they someday will.

The field of longevity pharmacology is growing

The number of compounds that have been shown to increase longevity in preclinical models is growing exponentially: it was approximately 300 in 2005, 1300 in 2015, and most recently to 2000 in 2020. Meanwhile, the discovery of longevity-associated genes has plateaued, following an exponential growth until approximately 2010 before transitioning to a slower growth over the last decade. Dr. Magalhães believes that there are probably many more longevity genes left, but the incentives for their discovery are reduced since most newly discovered genes now tend to eventually lead towards already known pathways.

The number of longevity companies has also doubtlessly increased dramatically, although this is harder to subjectively measure, as it is difficult to define what makes a company longevity-focused. Most of these companies deal with the hallmarks of aging, most notably oxidative stress and mitochondrial dysfunction, cellular senescence, and pathways implicated in caloric restriction, such as mTOR. The acquisition of longevity companies by big pharma, for example the purchase of Alkahest by Grifols, is also just beginning to occur. One concern, Dr. Magalhães notes, is the lack of strategic diversity. It is possible that too much weight is being put on these areas despite the much broader range of potential strategies.

Recently, the field has also seen its first clinical failures, a notable rite of passage for all new fields of medicine. In 2019, ResTORbio’s mTOR inhibitor RTB101 failed its Phase 3 trial for a lung disease, and Unity Biotechnology’s senolytic UBX0101 failed to meet its endpoints in osteoarthritis just last year. A myriad of challenges can complicate translation, such as a lack of genetic diversity in preclinical models, pathways that are not conserved between species, and the selection of proper primary endpoints. However, the list of ongoing clinical trials is constantly growing, with active studies including COVID, macular degeneration, frailty, and neurodegenerative diseases. The TAME trial of metformin represents a pivotal proof-of-concept study, which may pave the way for future therapies aiming to broadly target longevity in their applications to the FDA rather than any specific disease. Interest has also been growing in off-label prescriptions and nutritional supplements.

There has also been a ramping up of computer-based methods being applied to the field of longevity. Bioinformatics, machine learning and artificial intelligence, -omics approaches, and large public databases are just beginning to be fully utilized. These techniques may someday improve our abilities to predict the outcomes of clinical trials. They also aim to identify candidate drugs and biomarker and may eventually play a role in the application of personalized, precision medicine.

Conclusion

When taken as a whole, these trends characterize a vibrant, growing longevity industry in its early maturation stage. There are many parallels to the early days of some fields of pharmacology that are now well established, such as cancer and heart disease. While the future is unknown, Dr. Magalhães gives us plenty of reasons for optimism.

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Literature

[1] João Pedro de Magalhães. (2021). Longevity pharmacology comes of age. Drug Discovery Today, in press. https://doi.org/10.1016/j.drudis.2021.02.015

Date Posted: February 23, 2021

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SIRT3 Replenishment Reverses Lung Fibrosis in Mice

Scientists have successfully reversed persistent lung fibrosis in mice by overexpressing the SIRT3 protein in lung macrophages [1].

Fibrosis: not knowing when to stop

Fibrosis may be the true apex predator of humanity. According to one study, fibrotic diseases that cause organ failure are responsible for around 45% of all deaths in the United States [2]. Aging is a major risk factor for fibrosis.

Like many harmful biological processes, fibrosis is a beneficial process under normal circumstances: it is a repair mechanism that is triggered by injuries. While we are young, a balance exists between fibrosis and the subsequent regeneration of tissues. With age, our regenerative abilities falter, and fibrosis goes on unchecked.

One fibrotic disease has recently made headlines in the context of the SARS-CoV2 pandemic: idiopathic pulmonary fibrosis (IPF). Severe COVID-19 and IPF share major risk factors, including age, along with some symptoms. A study in Lancet suggests that these two diseases may also share treatments [3].

An inhaled delivery mechanism

This time, a group of researchers identified a potential target for IPF therapy that may sound familiar: SIRT3, a member of the sirtuin family of proteins. Sirtuins are highly evolutionary conserved proteins known for their effects on aging. Most of them reside in the nucleus, where they perform various maintenance tasks, such as histone deacetylation required for DNA stability. However, three members of the family are located in mitochondria. One of them, SIRT3, is a mitochondrial deacetylase, and its overexpression has been associated with increased longevity in humans [4].

The researchers observed a considerable reduction of SIRT3 expression in the lungs of IPF patients, especially in patients with rapid progression of the disease. Findings were similar in mice with IPF-like lung injury. Consistent with the normal behavior of fibrosis, young mice gradually recovered their regenerative potential and SIRT3 levels, while mice with genetically induced accelerated aging did not. Most importantly, the scientists were able to reverse persistent lung fibrosis in aged mice by overexpressing SIRT3 via airway delivery, for which they used SIRT3-coding plasmids (small, circular DNA fragments).

Myofibroblasts and macrophages

To understand the mechanism behind this effect, the researchers started with myofibroblasts, which differentiate from resident fibroblasts. These are key effector cells that respond to lung injury and orchestrate repair. It appears that downregulation of SIRT3 is a prerequisite for myofibroblast differentiation.

Fibrosis resolution is associated with myofibroblasts undergoing apoptosis. To put it simply, after having finished their job, myofibroblasts have to die. SIRT3 deficiency in aged organisms makes these cells become resistant to apoptosis and opt for senescence instead. SIRT3 overexpression appears to alleviate this problem, while SIRT3 silencing exacerbates it. The researchers were able to show that SIRT3 achieves it indirectly via another protein, FOXO3A, a transcription factor that is associated with longevity. Interestingly, simple overexpression of SIRT3 in fibroblasts in vitro could not recapitulate all the effects of delivering SIRT3 via airway – particularly the FOXO3A upregulation. This led the researchers to hypothesize that these effects were achieved at least in part via intercellular communication. After running several cell type models, the scientists found that the effect is best explained by bringing macrophages into the equation.

In relation to fibrosis, macrophages have two strikingly different phenotypes: they can be either pro-fibrotic or anti-fibrotic [5]. In this study, macrophages seemed to act as the primary receivers of the SIRT3 plasmids. The researchers suggest that SIRT3 regulates changes in the fibrotic phenotype of macrophages. According to this hypothesis, SIRT3 downregulation in macrophages makes them pro-fibrotic. Pro-fibrotic macrophages then induce myofibroblast differentiation via cell-to-cell communication. In younger organisms, this process, when no longer needed, resolves itself by myofibroblasts undergoing apoptosis. This requires upregulation of SIRT3, but the age-related SIRT3 deficiency stands in the way. When SIRT3 is artificially supplemented in macrophages, the balance is restored: they acquire the anti-fibrotic phenotype and drive myofibroblasts towards apoptosis. It is possible that this effect is complemented by the direct uptake of SIRT3 by myofibroblasts themselves.

Conclusion

While the mechanisms by which SIRT3 restitution leads to the results demonstrated in this study need to be investigated further, there is no doubt that this research has contributed a great deal to our understanding of fibrosis and of ways to alleviate it. Their findings also confirm the importance of SIRT3, cellular senescence, and apoptosis for various aging processes. Any new insights into lung fibrosis are also highly relevant in the context of COVID-19.

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Literature

[1] Rehan, M., Kurundkar, D., Kurundkar, A. R., Logsdon, N. J., Smith, S. R., Chanda, D., … & Thannickal, V. J. (2021). Restoration of SIRT3 gene expression by airway delivery resolves age-associated persistent lung fibrosis in mice. Nature Aging, 1-13.

[2] Zhang, F., Ayaub, E. A., Wang, B., Puchulu‐Campanella, E., Li, Y. H., Hettiarachchi, S. U., … & Low, P. S. (2020). Reprogramming of profibrotic macrophages for treatment of bleomycin‐induced pulmonary fibrosis. EMBO molecular medicine, 12(8), e12034.

[3] George, P. M., Wells, A. U., & Jenkins, R. G. (2020). Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. The Lancet Respiratory Medicine.

[4] Bellizzi, D., Rose, G., Cavalcante, P., Covello, G., Dato, S., De Rango, F., … & De Benedictis, G. (2005). A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics, 85(2), 258-263.

[5] Zhang, F., Ayaub, E. A., Wang, B., Puchulu‐Campanella, E., Li, Y. H., Hettiarachchi, S. U., … & Low, P. S. (2020). Reprogramming of profibrotic macrophages for treatment of bleomycin‐induced pulmonary fibrosis. EMBO molecular medicine, 12(8), e12034.

Date Posted: February 22, 2021

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Humacyte in Deal to Develop Prosthetic Vasculature

Tissue engineering company Humacyte is about to make a special purpose acquisition company (SPAC) deal in order to go public. The company is developing bioengineered Human Acellular Vessels (HAVs), which provide prosthetic vasculature to support the repair, reconstruction, and replacement of blood vessels damaged by injury or disease.

What is a SPAC?

A special purpose acquisition company, or SPAC, is in essence a shell company created by investors with the singular purpose of raising money via an initial public offering (IPO) to eventually acquire another company.

A SPAC has no commercial operations, nor does it make products, and it does not sell anything. In fact, a SPAC’s only assets are usually the money raised within its own IPO, according to the SEC. A SPAC is typically created, or sponsored, by a group of investors, Wall Street professionals, or hedge funds. It is even possible for high-net-worth individuals to create SPACs, and Richard Branson is one such recent example of this practice.

This deal comes as Humacyte seeks to move from being a late-stage clinical company to a commercial one. The SPAC deal could potentially make it easier for Humacyte to go public compared to traditional methods. An advantage of taking the SPAC route over the traditional IPO is that it gives the company more time to pitch to investors and potentially get them on board.

More about Humacyte

It recently announced it is going public through a merger with a SPAC, Alpha Healthcare Acquisition Corp, which will be providing the funds. The SPAC will acquire Humacyte in a transaction slated to close during the second quarter of this year. As part of the all-stock deal, the combined company will get up to $100 million from the SPAC as well as $175 million via a private funding round. The company will trade on the Nasdaq Capital Market under the ticker symbol HUMA.

This news is a particularly interesting development as the HAV has the potential to be universally implantable, as it did not generate a foreign body or immune response in human clinical trials. This gives HAV an off-the-shelf versatility and has the potential to be repopulated with the patient’s own vascular cells, thus creating living vasculature that is functionally similar to natural tissue.

Prior to this deal, the SPAC looked at a number of companies, but with three Phase 3 trials in progress, plenty of late-stage data, a product with wide potential applications, and an in-house manufacturing process that can operate at scale, Humacyte was just too tempting to pass up on.

Humacyte holds 87 patents with another 21 pending, a proprietary human cell bank and tissue engineering methods, and an estimated market of $150 billion or perhaps higher for its products. Its initial products will consist of HAVs for treating trauma repair, arteriovenous access for hemodialysis, and peripheral arterial disease.

The transaction values Humacyte at a pre-money valuation of $800 million, with existing Humacyte shareholders converting 100% of their equity into equity in the combined companies. Humacyte is slated to have a market capitalization of $1.1 billion pending closure of the transaction.

RMAT comes of age

We talked about regenerative medicine advanced therapy (RMAT) back in November 2017, when the FDA announced a comprehensive policy framework for the development and oversight of regenerative medicine products, including novel cellular therapies. Both draft guidance documents had 90-day comment periods, and at the time, we joined forces with the Niskanen Center to submit comments to the FDA to ensure that the voice of the community for longevity and healthy life extension was heard.

At the time, we were hopeful that the RMAT framework would pave the way for pioneering new technologies for aging, and we were delighted to learn that the Humacyte HAVs were given the RMAT expedited review designation by the FDA. It is particularly satisfying to finally see the RMAT framework beginning to usher in the kinds of technologies that could contribute to ending age-related diseases.

The company has also received a priority designation for the treatment of vascular trauma by the U.S. Secretary of Defense. This is great news for the military, as the system can be used when needed and simply taken out of storage, removed from its biobag, and used to potentially save a wounded person’s life without the fear of immune rejection and the need to administer immunosuppressive drugs. It expects this program to finish phase 3 evaluation and intends to file for FDA approval in 2022, and it could be used to treat battlefield trauma in the near future.

Conclusion

This could pave the way for more companies to take the SPAC track, and it could be very beneficial to companies working on aging. It’s also good to see how RMAT is starting to support the next generation of medical technologies like the Humacyte HAV system, and if approved, it has the potential to change how we treat heart disease and trauma. The platform is highly flexible and can operate at scale, which would mean costs could be kept down and access easier. The system has great potential, and the company has other tissues and organs in mind for future development, including a pancreas and coronary artery bypass grafts. We wish the staff at Humacyte all the best with their endeavors and hope that the SPAC deal proves to be useful in bringing this technology to market.

Date Posted: February 19, 2021

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Atrophy of the Neuronal Circadian Clock Is a Disease of Aging

Today, researcher Victor Bjoerk talks us through his latest published paper, in which he describes a neurodegenerative disease that affects the circadian clock.

A circadian clock disease

With aging, the brain runs into multiple issues; however, some are more serious than others and cause disease symptoms throughout the body. While aging of some brain areas, such as the substantia nigra, leads to well-known diseases such as Parkinson’s, other areas have not received disease classifications.

In my new paper, I came up with the idea of labeling the aging damage of another brain region, the suprachiasmatic nucleus (SCN), as a disease [1]. The SCN is a small cluster of about 10,000 neurons that regulate sleep and circadian rhythms throughout the whole body. This new disease is called Circadian Clock Neuronal Senile Atrophy (CIRCLONSA) syndrome, and it is important to classify it as a disease so that efforts to defeat it can receive proper research focus and funding for biotechnological entrepreneurship.

The suprachiasmatic nucleus (SCN) in the brain is the master regulator of the circadian clocks throughout the human body. With increasing age the circadian clock in humans and other mammals becomes increasingly disorganized leading to a large number of more or less well categorized problems. While a lot of aging research has focused on the peripheral clocks in tissues across organisms, it remains a paramount task to quantify aging of the most important master clock, the human SCN. Furthermore, a pipeline needs to be developed with therapies to mitigate the systemic cellular circadian dysfunction in the elderly and ultimately repair and reverse aging of the SCN itself. A disease classification for the aging SCN, Circadian Clock Neuronal Senile Atrophy, (CIRCLONSA syndrome), would improve research funding and goal-oriented biotechnological entrepreneurship.

Aging of the SCN contributes to the problem of elderly getting good sleep since it misaligns the signals to the brain’s sleep center, leading to waking episodes during the night and low quality of sleep in the elderly. However, there are many more issues; for example, cell division across the whole body is controlled by circadian rhythms, which should contribute to an increased risk for cancer with old age due to cells receiving the wrong signals of when to divide. An aging SCN also contributes to sarcopenia and generalized metabolic dysfunction.

It is well known that shift workers are more prone to many diseases, and, for this reason, it is a good idea to keep healthy habits when it comes to getting good sleep during regular, daylight hours. However, aging makes the SCN decline, which means that old people, in many ways, get the same metabolic problems as shift workers, which is on top of other aging damage.

While research has been going on in this area for several decades, there has been no attempt to address this by developing a pipeline of therapies. However, there exists proof of principle that the SCN is very important, as transplantation of young SCN tissue to aged hamsters led to a life extension of 12% in a study performed in the 1990s.

Several things inside the SCN make it deteriorate with age; for example, ion signaling is disturbed due to membrane changes in the aging cells. Also, they are filled with lipofuscin, which is a mixture of lipids and fats that take up space inside the aging brain. The different neurons inside the SCN have specialized functions, with different neuropeptides responsible for synaptic transmission; when this ability is lost with age, it produces an erratic circadian rhythm.

What can we do to address this condition?

More drugs affecting circadian hormones might be developed to help improve the general health of the elderly with everything from sleep to cancer risk. There are already some relevant pharmaceutical compounds, such as CLK8, which improves circadian oscillations [2], and SR9009. Interestingly, SR9009 is listed as being a potential doping compound, since it increases muscle mass. It also improves metabolism through increasing mitochondrial count through interaction with the circadian clock [3].

I also propose using a brain pump to take over the functions of the aging SCN to restore the circadian signaling in the body to youthful levels; since the SCN communicates with many brain regions, it is important that any intervention can generate effects within the brain.

What would constitute a solution to the problem would be a full repair approach that repopulates the lost neurons and/or reverses damage to the neurons themselves.

When trying to cure age-related diseases, some problems are going to be more important than others to address in order to achieve a prolonged healthspan/lifespan. In this paper, I argue that CIRCLONSA should be seen as a major disease affecting the whole body; the restoration of this brain clock would improve many different issues at once in the aging body.

Yes I will donate❤️

Literature

[1] Björk V. Aging of the Suprachiasmatic Nucleus, CIRCLONSA syndrome, implications for regenerative medicine and restoration of the master body clock. Rejuvenation Res. 2021 Feb 11. doi: 10.1089/rej.2020.2388. Epub ahead of print. PMID: 33573456.

[2] Doruk YU, Yarparvar D, Akyel YK, et al. A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude. J Biol Chem. 2020;295(11):3518-3531. doi:10.1074/jbc.RA119.011332

[3] Solt LA, Wang Y, Banerjee S, et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature. 2012;485(7396):62-68. Published 2012 Mar 29. doi:10.1038/nature11030

Date Posted: February 18, 2021

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The NIA Is Funding Clinical Trials Against Aging

The National Institutes of Aging in the United States, a component of the National Institutes of Health, is funding clinical trials for interventions that directly affect the root causes of age-related diseases.

Direct funding for trials against aging

Probably the most important and interesting part of this Funding Opportunity Announcement (FOA) is that the NIA specifically mentions “multiple chronic conditions” caused by the processes of aging along with more conventional trials that are targeted directly at specific downstream effects of aging.

This wording represents an enormous change, and a potential enormous opportunity, for aging researchers seeking to test their products in human clinical trials, as it addresses one of the largest concerns: endpoints. Companies that are creating rejuvenation biotechnology interventions must develop their products to target individual diseases in order to be approved by the FDA. While that is still the case, this particular FOA is intended to promote broader research that does not necessarily target individual diseases as endpoints.

What is, and isn’t, this funding for?

This FOA does not apply to stem cells (which are already heavily researched), nor does it allow the funding of “definitive efficacy or safety trials”. It is intended for early-stage, investigative human clinical trials into the feasibility of interventions against the root causes of aging, including supplements, biologics, new drugs, and existing drugs.

The NIA intends to fund Stage 1 trials that assess safety and tolerability while analyzing the pharmacological effects of interventions, Stage 2a proof-of-concept pilot studies that determine on- and off-target effectiveness along with interactions with other drugs, and Stage 2b studies that will serve as the basis of future trials that determine efficacy more definitively.

This funding is open to a wide variety of groups based in the United States, including private corporations, state government entities, and public institutions such as universities.

Applicants are expected to propose trials of new and repurposed molecular entities in healthy volunteers or target patient populations that are designed to do the following:

Assess safety and tolerability, characterize the dose-limiting adverse reactions, or determine the maximum tolerated dose

Evaluate pharmacokinetics, pharmacodynamics, or interactions with co-existing conditions and medications

Evaluate select characteristics of safety and efficacy such as dose-response and routes of administration

Assess degree and specificity of molecular and cellular target engagement, and/or off-target effects

Generate evidence of early clinical efficacy and safety of interventions on intermediate clinical outcomes and/or predictors of clinical outcomes

Conclusion

While we won’t see any results from any trials funded by this FOA for quite some time, as the earliest such a trial can begin is in April 2022, this is incredibly good news for the longevity community. Many people have been hoping that the federal government of the United States would directly fund research into human clinical trials of longevity itself, and that day appears to have come. While this FOA certainly does not equate to a full-throated endorsement of rejuvenation biotechnology nor life extension as a whole, it represents the fact that the NIA is now officially willing to put federal dollars towards truly solving a problem that causes tremendous harm and already soaks up an enormous percentage of the federal budget: aging.

Date Posted: February 17, 2021

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Replacing Aging With Jean Hébert

Replacing Aging by Jean Hébert is the latest longevity book published for public consumption. While books such as these seem to be coming out more regularly, readers who have already tackled David Sinclair’s Lifespan, Nir Barzilai’s Age Later, or Aubrey De Grey’s Ending Aging shouldn’t simply dismiss Replacing Aging as something they’ve already seen. While Dr. Hébert is another scientist in the field of longevity who is decoding his research for the general public, he takes a much different approach to the field that interested readers likely have not seen elsewhere.

The case against drugs

Replacing Aging takes a heavily critical stance of the pharmaceutical approach most commonly employed by most longevity researchers. It only briefly skims over the motivation for fighting aging and counterarguments to common concerns about lifespan extension. As such, this book would not be a great medium to introduce people to the field, but others have already covered this in detail, and, as Dr. Hébert professes, it is not his area of expertise. Next, the book covers the processes of aging, including the different types of damage and the repair mechanisms that our bodies utilize in response. A major focus is placed on the sheer complexity of this system, which is shown to be staggering, based on what we do know, and potentially even more complex than that, based on what we don’t. This is the crux of the following, most controversial, portion of the book: why drug development won’t meaningfully affect aging.

There are many types of molecules in the body, multiple types of damage to each of those, and multiple ways of repairing each type of damage. Preventing or fully repairing one type of damage would not necessarily stop aging if other types were able to continue. The difficulty of targeting even one type of damage is also highlighted, with complex and tightly regulated molecular pathways at the center of each. Pathways usually overlap, sharing molecules with other pathways and making them difficult to modulate without off-target effects. Furthermore, many of these pathways do not simply turn on or off, but the magnitude must also be considered. Too much or too little expression of a molecule can result in a therapy that does more harm than good. Based on these arguments, it is not unreasonable to posit that all the “low-hanging fruit” in the world of pharmaceutical treatments have already been picked.

Alternatives to the pharmaceutical approach

The book then presents a competing thesis: replacement. Like a car, which can be driven indefinitely if its parts are replaced, the cells and tissues of our bodies may also someday be replaceable. Tissue engineering and regenerative medicine have made great strides since the turn of the millennium. Our ability to manipulate cells and manufacture tissues, while not yet reaching the clinic, has improved dramatically. Technologies such as induced pluripotent stem cells, bioprinting, and bioreactors may someday allow for lab-grown organs. The biggest hurdles in the way of replacement strategies are engineering problems rather than biological ones. However, there’s one big thorn in the side of this strategy, which also brings us to the focus of Dr. Hébert’s research: the brain.

As our thoughts and memories are contained in the brain, we would hardly be satisfied being replaced with a lab-grown brain. This is not a fatal flaw to replacement as a strategy, as much of the rest of the book covers the most promising research in replacing brain tissue in a way that would preserve our senses of self. The plastic brain is constantly remodeling itself as we form new memories and forget old ones. Removal of one part of the brain is remarkably compensated for by other regions. This slow replacement could occur on the macro scale surgically or on the micro scale through cell transplantation. The book concludes on more philosophical considerations, which demonstrate that it would be possible to preserve our senses of self while simultaneously making our brains younger.

Is drug development doomed to fail?

The drug development process is no stranger to criticism. Many other experts have made similar arguments over the years, although not usually in the context of lifespan extension. One ray of hope for longevity researchers has been that targeting aging may get at the underlying cause of many diseases and thereby succeed where the individual disease approach has failed. However, the possibility remains that drugs targeting aging will never be able to meaningfully extend the lives of patients or that they may only extend healthspan but not lifespan. The complexity of aging is one very real reason for this possibility. Replacing Aging highlights this prospect in a logical, well-written, and compelling fashion.

It is also a message that I believe more people need to hear. I did my PhD in tissue engineering but recently made a major switch to study cellular senescence in the brain. Because of this, reading Replacing Aging was deeply personal to me. It was a bizarre experience to read, as my new field was criticized in favor of the field I had just moved away from.

The future remains a mystery, however, and I found the certainty with which the book dismissed the pharmaceutical approach to be particularly flawed. The impression readers are left with is that success with drug-based treatments is impossible and that somehow we already know this without conducting clinical trials. We should not neglect recent innovations in drug development nor the possibility for future innovations. A lot can change in 10 years’ time outside the field of drug development as well, for example in artificial intelligence, which may impact its prospects.

In the same vein, the book fails to concede that replacement may also ultimately be an unsuccessful strategy. Replacement is not simply an engineering problem – it is a bioengineering problem. The same complexity that hinders the drug-based approach may prove too great for replacement as well. Additionally, transplanted cells do not fare well in an aged microenvironment. For example, transplanted organs quickly catch up to their hosts when old recipients receive organ donations from young donors. Further, older individuals do not tolerate and recover from surgery nearly as well. There is much we simply still do not know about which strategies can and cannot succeed.

Where do we go from here?

Ultimately, the most important question is whether the field needs to pivot in order to maximize the chances of successful treatments. In this respect, Replacing Aging crucially highlights the divide between tissue engineering and longevity research. Nearly all translational age-related research is focused on drugs. Similarly, nearly all translational tissue engineering research is disease-specific rather than aging-focused.

The National Institute on Aging (NIA) and the American Federation for Aging Research (AFAR) rarely fund replacement strategy projects. Tissue engineering is instead funded through a variety of other agencies based on individual diseases. This divide may be a major reason why tissue engineering researchers largely ignore aging. On the other hand, the research budget for aging is already miniscule compared to disease-specific approaches. The projects they currently fund do show significant potential, especially if we accept that we cannot predict what strategies will ultimately be successful. It is difficult to accept that we must divert precious funding from all drug-based approaches.

So, how much should we focus on drug-based or replacement-based approaches? Simply put, the longevity field needs diversity and as many shots on goal as possible. This means a greater incorporation of replacement strategies without a complete abandonment of drug development. It also means that the funding of “aging” research should not be not limited to the NIA. Since aging affects every system in the body, more divisions of the NIH should be funding these types of projects, making it a larger slice of the overall budget. Finally, we need to begin breaking down the silos between the tissue engineering and longevity fields. Dr. Hébert’s work is a sterling example of incorporating these two distinct but complementary areas. Hopefully, Replacing Aging will promote collaboration and encourage others to follow a similar path.

Yes I will donate❤️

Date Posted: February 16, 2021

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Lessons from Longevity Therapeutics 2021 – Part 4

This is the final installment in our coverage of Longevity Therapeutics 2021, a conference that brought together some of the biggest names in longevity research. Read the previous parts here, here, and here.

Dr. Andrei Gudkov – Chief Scientific Officer, Genome Protection

Andrei Gudkov gave a talk on what he and many others consider a major cause of aging: retrotransposons. These repetitive elements, which constitute more than half of our DNA, are the remains of ancient viruses piggybacking on our genes. Most of them are inactive: they only get copied along with the rest of our DNA during cell division. Tightly wound into heterochromatin, they became benign. However, sometimes a retrotransposon breaks free and proliferates by coding for the enzyme reverse transcriptase, which then causes more of the retrotransposon’s copies to be inserted elsewhere in the genome. According to Gudkov’s theory, this retrobiomic activity accelerates with age, hampering the ability of the affected cells to function and triggering an immune response, which results in inflammaging. Most but not all such cells undergo senescence, which is why removing only senescent cells does not solve the problem entirely. Research links the longevity of various mammalian species to their levels of retrobiome activity. If the theory is solid, aging can be considered, in part, a viral disease and may potentially respond to anti-viral treatments such as vaccination. Retrobiome activity also increases dramatically in cancer cells, boosting their mutation rate and helping them evade treatment.

Gudkov’s group has been making steady progress. In mouse experiments, cancer-prone animals treated with a reverse transcriptase inhibitor showed greatly increased survivability. In another study, mice that received a prototype of an anti-retrobiome vaccine demonstrated decreased frailty. This is an ongoing study, and Gudkov still does not have data on the survival rates of the mice. With his non-profit called Vaika, Gudkov also studies retrotransposons in dogs. Dogs exhibit especially high levels of retrobiome activity due to their morphological diversity, and inhibiting this activity can potentially lead to a meaningful increase in our precious companions’ lifespans. Check out this expansive interview that Dr. Gudkov gave us in 2018.

Dr. Lewis Gruber – Chief Executive & Scientific Officer, Siwa Therapeutics

Siwa Therapeutics, founded and led by Dr. Lewis Gruber, is a hot name in longevity research. In the MIT Technology Review article “10 Breakthrough Technologies of 2020”, the company was named a key player in the anti-aging field. Read our interview with Dr. Gruber from 2020.

Gruber’s presentation echoed Gudkov’s in that the longevity industry should look beyond targeting senescent cells, and Gruber and Gudkov both believe that their approaches can be used across a wide spectrum of age-related diseases.

Siwa has developed the monoclonal antibody 318H. It selectively targets the eponymous biomarker, which is abundant in cells exhibiting high levels of glycolysis and oxidative stress. The antibody tags dysfunctional cells for immune destruction, such as senescent and cancerous cells, other oxidatively stressed cells, and infected cells (including cells infected with SARS-CoV-2, the virus that causes COVID-19).

Gruber claims that 318H can be used against virtually all cancers. Siwa is currently focusing on “life-threatening diseases with unmet medical needs”, such as pancreatic cancer, to be eligible for FDA fast-tracking. In recent mouse trials, 318H drastically decreased senescent cell load, to a level lower than in young healthy controls. It also reduced metastasis in a murine model of triple-negative breast cancer. Siwa expects to file an IND (investigational new drug) application by the end of the year.

Dr. Thomas Hughes – President and CEO, Navitor Pharmaceuticals

Rapamycin is the first and most well-studied small molecule drug that can extend lifespan in animals. Years ago, it was hailed as a potential game changer in the longevity field. Unfortunately, since then, numerous studies have confirmed rapamycin’s toxicity, which severely restricts its use. As scientists have learned, rapamycin is toxic because it inhibits not only the harmful activity of mTORC1 (mechanical target of rapamycin complex 1) but also the beneficial activity of its sibling, mTORC2. This leads to immune suppression, deterioration of kidney function, and other deleterious effects.

Since 2016, Hughes and his team have been exploring ways to overcome this limitation. They have developed a new class of rapamycin analogs, the most promising of them being NV-20494. This compound can selectively engage mTORC1 without interfering with mTORC2.

Hughes’ team chose to target kidney diseases, and as many other companies have, Navitor had to devise a strategy to accelerate the introduction of their new drug. The company plans to target a rare genetic condition (polycystic kidney disease – PKD) first and, after receiving authorization, to expand to the more prevalent chronic kidney disease.

Multiple drivers, many of them age-related, increase mTORC1 activity in the kidneys of PKD patients, including high levels of glucose, lipids, and insulin along with hypertension and lack of exercise. The disease causes renal fibrosis, formation of cysts, and gradual loss of kidney function.

Navitor has yet to enter Stage 1 trials, which are expected to begin later this year, but the preliminary results look promising. In pre-clinical trials, NV-20494 reduced cyst volume in vivo in mouse cells and in vitro in human 3D cell culture, normalized gene expression, and drove down fibrosis and inflammation markers in the kidney. According to Hughes, this is just the beginning. If Navitor can deliver on its promise, we might witness a second rapamycin boom.

Samuel Agus, M.D. – Chief Medical Officer, Biophytis

Biophytis is a company that originated in Sorbonne University. It is headquartered in Paris and is developing plant-derived anti-aging compounds. Its lead candidate drug, BIO101, normalizes angiotensin production, which can help reduce hypertension, inflammation, and fibrosis. The drug is currently being tested against sarcopenia in a Stage 2 clinical trial to target ACE2 (angiotensin-converting enzyme 2) by facilitating the conversion of harmful angiotensin-8 to beneficial angiotensin 1-7. ACE2 is also the receptor that SARS-CoV-2, which causes COVID-19, uses to invade cells, which is why BIO101 is currently undergoing trials in patients with severe respiratory symptoms.

However, the focus of Agus’s talk was on various issues specific to clinical trials in the longevity field. For starters, most age-related diseases tend to advance slowly, so trials may take too long for the attention span of pharmaceutical companies, let alone venture capitalists. There is also a question of when to intervene. Researchers prefer to intervene early to have the most impact, but at this stage, the scarcity of symptoms can complicate matters.

Choosing participants can be a daunting task as well. Researchers must strike a balance between stricter and looser criteria, choosing people who are more likely to respond to treatment without making trials too specific. An elderly population presents additional challenges. First, changes in the participants’ conditions are unavoidable, especially in long-haul studies: older participants usually have additional medical problems that can lead to deterioration. Such changes can also be beneficial, if a participant becomes physically active, switches to a healthier diet, or starts receiving a new treatment, but they still muddy the waters for researchers. Second, over long periods of time, the very criteria of the disease can change, jeopardizing the study’s relevance and perspectives.

If you would like to know more, cou can read about the other days below:

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Date Posted: February 16, 2021

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Developing Our Ethics Code of Longevity Journalism

When lifespan.io was started in 2014 as a crowdfunding platform, we didn’t really know that we would become a news outlet covering longevity research. We didn’t plan to be one. However, after running our first crowdfunding campaign, we realized that public awareness of aging research is extremely low, and if we want to direct more funds into aging research, this has to change. This is how our journey as a news outlet begun.

Empowering the public

Our goal was, and continues to be, to publicly share our dream of healthy longevity and the promise that rejuvenation biotechnology holds. We want to give the public an opportunity to witness the biotechnological revolution and become part of the decision-making process related to the clinical implementation of longevity therapies. To do so requires a lot of work and a systemic approach.

Fact-checking habits

When we started our news outlet in 2016, there was a strong internal understanding that whenever we discuss healthy longevity, we should create fact-based articles that explain the science as accurately as possible so as not to mislead the public and avoid overpromising. It became our very first rule to fact-check, stay neutral, and provide a link to the original scientific publication whenever we use data from it.

As we grew, our readers became our best coaches. Whenever a conclusion was too optimistic, or the assumption too far-fetched, we did our homework to improve the material. Whenever an article was hard to parse, and people complained about too much heavy science, we worked on our skills of science popularization.

Sticking with the principles of education

Very early on, the analysis of sociological studies focused on the public perception of longevity research and life extension led us to formulate our next rule: telling each story in the right way. Most people probably don’t remember their biology classes at school, and they may not know how science explains aging and the connection between aging, the root mechanisms of damage accumulation, and age-related diseases. Without those basics, it is hard to understand the potential of therapies that target the hallmarks of aging in order to reverse biological age and restore youthful rigor.

A link between longevity and frailty, however, is a common belief, as the only examples of extreme longevity that we currently have are supercentenarians. The problem is that nobody can yet become a supercentenarian and still look like a 30-year-old, so extreme old age is not attractive. People want to live longer only if they keep their health and independence and can live full lives, and we have to always underline that this is exactly what longevity researchers are working on. This is how the soft messaging rule was developed: we explain aging and the concept of rejuvenation biotechnology first, and then we show people that life extension is a beneficial side-effect of improved health. Luckily for us, by 2016, animal studies provided proofs-of-concept in abundance.

Maintaining transparency

As the field progressed, more and more biotechnology companies were founded. Being essentially an advocacy group, we celebrated such news, and we really wanted to give them as much exposure as possible. It led to another serious question: how do we maintain the balance between newsmaking and promotion? By default, newsmaking must be independent and free from biases. In response to many requests for free promotion, and to keep editorial decisions free from external influences, we introduced our advertisement policy and started to use disclaimers to make it easier for the reader to take into account the partnerships that stand behind some types of content.

Do no harm

Later on, a new challenge emerged: the rise of biohackers. People around the world started using experimental treatments on themselves and talking about their experiences. During a number of public events in which our team members mentioned self-experimentation with supplements and drugs that potentially have anti-aging effects, we realized that, in practice, people get so excited about interventions against aging that they buy and start using everything that is available on the market without any sort of medical advice or control. Despite the fact that we consider self-experimentation an important part of scientific research, when unprepared people do it, it may be risky, and we don’t want someone to get hurt. Therefore, we decided to always put warnings on our materials about supplements and drugs, advising people to be cautious, get proper diagnostics, and consult with medical advisors before conducting any kind of intervention.

Pyramid of evidence

2018-2019 appeared to be a turning point. A lot of large media publications started writing about aging research, often in a positive way. However, there was a worrying trend: mass media didn’t really draw a line between animal and human trials. Titles like “The first case of aging reversal” or “Biological immortality is close” were often introducing articles about modification of aging in worms and mice. We at lifespan.io have been avoiding sensationalism and clickbait from the beginning, but we realized that explaining the pyramid of evidence and underlining the limitations of animal data is useful, since the vast majority of interventions in animals do not translate directly to humans.

Contextualized reporting

The latest, biggest challenge came together with the progress of the open-access approach. The open-access movement advocates for making the results of research available to the public without any paywalls and as fast as possible. This way, even organizations and individuals in the least developed and poorest countries can get access to valuable data to improve human life. The pre-prints (early, raw versions of scientific articles) started to get published online, often in public depositories not associated with any scientific publications, which increased the workload on the people performing fact-checking. To evaluate the scientific accuracy of each article and the cohesion between its findings and existing knowledge, a new level of scientific expertise became essential for accurate news reporting. In response, we created an internal process to improve fact-checking, and we have started to involve writers with strong research backgrounds.

Setting up standards

After five years of writing news, we came to the conclusion that longevity journalism demands its own code of ethics. Telling people about rejuvenation biotechnology is too important and too complicated, and the rules that we first developed for ourselves can help set standards for the industry. I wrote the first draft, and over several iterations, we updated it to include the situations that our team of writers consistently faces. Today, we present the lifespan.io Ethics Code of Longevity Journalism in order to help our fellow journalists navigate the field with more confidence.

New challenges will emerge that will require an even more sophisticated approach on our part in order to remain a credible source of information for the longevity community and the world. Therefore, we welcome everyone who is involved in professional journalism to share suggestions and constructive criticism of this Code with us. There is no ceiling to perfection, and we welcome your input.

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Date Posted: February 15, 2021

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Proposing Gerobiotics as a New Gut Microbiome Research Field

The aging of the microbiome, the collective bacteria, fungi, protozoa and viruses that live on and inside our bodies, has become a popular research topic in recent years.

The microbiome appears to influence aging

There has been increasing interest in the influence of this microbial community, especially those living in the gut, in the context of aging and disease.

The gut microbiome is a complicated community of microbial life that constantly changes and shifts in response to diet, lifestyle, and other stimuli. Studies have shown that there is a great deal of crosstalk between the microbiome, the immune system, and other parts of the metabolism. It is becoming increasingly clear that the microbiome is a mediator that stands between diet and health.

Unfortunately, as we age, the microbiome changes with a tendency for beneficial bacteria to decline and for harmful ones to increase. An increasing number of researchers are engaged in investigating those changes and countering them, but despite considerable progress in the last few years, understanding these changes is still a relatively new area of research that has yet to reach maturity.

The researchers of today’s highlighted review have proposed that a new term, “gerobiotics“, be used to describe the bacteria that beneficially influence the aging processes to potentially slow, delay, or reverse some aspects of aging and increase the healthspan or even lifespan of the host [1].

The review provides a summary of the past research in this field and also the needs, challenges, and direction that this proposed gerobiotics field might take. The researchers also consider and suggest how biomarkers and gerobiotic interventions might be developed as part of this new field.

Aging is recognized as a common risk factor for many chronic diseases and functional decline. The newly emerging field of geroscience is an interdisciplinary field that aims to understand the molecular and cellular mechanisms of aging. Several fundamental biological processes have been proposed as hallmarks of aging. The proposition of the geroscience hypothesis is that targeting holistically these highly integrated hallmarks could be an effective approach to preventing the pathogenesis of age-related diseases jointly, thereby improving the health span of most individuals. There is a growing awareness concerning the benefits of the prophylactic use of probiotics in maintaining health and improving quality of life in the elderly population. In view of the rapid progress in geroscience research, a new emphasis on geroscience-based probiotics is in high demand, and such probiotics require extensive preclinical and clinical research to support their functional efficacy. Here we propose a new term, “gerobiotics”, to define those probiotic strains and their derived postbiotics and para-probiotics that are able to beneficially attenuate the fundamental mechanisms of aging, reduce physiological aging processes, and thereby expand the health span of the host. We provide a thorough discussion of why the coining of a new term is warranted instead of just referring to these probiotics as anti-aging probiotics or with other similar terms. In this review, we highlight the needs and importance of the new field of gerobiotics, past and currently on-going research and development in the field, biomarkers for potential targets, and recommended steps for the development of gerobiotic products. Use of gerobiotics could be a promising intervention strategy to improve health span and longevity of humans in the future.

Conclusion

This review is a welcome addition to the area of microbiome research, and it would be great to see the near-future emergence of a gerobiotics field that seeks to identify pro-longevity bacteria and ways to reliably introduce them into our bodies.

In the meantime, there are already potential solutions to the age-related decline of microbiome diversity, though they are not for the faint-hearted. Fecal transplants have seen some success in animal studies, in which samples of young microbiome are transferred to older individuals via fecal matter that contains enough beneficial bacteria to “seed” the aged gut [2].

It may also be possible for probiotics to deliver the correct mixture of pro-longevity microbes to the aged gut microbiome, though this area of research is poorly understood at this time, and success has been limited so far.

It also might be potentially possible for prebiotics to deliver microbial enzyme inhibitors to the aged gut microbiome in order to block or reduce the production of deleterious bacterial metabolites such as TMA, the precursor of TMAO, which is potentially linked to vascular aging. This is an appealing path, as it targets the problematic metabolites and sidesteps the complexity of needing to take into account the complex interplay of thousands of types of bacteria.

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Literature

[1] TSAI, Y. C., CHENG, L. H., LIU, Y. W., JENG, O. J., & LEE, Y. K. (2020). Gerobiotics: probiotics targeting fundamental aging processes. Bioscience of Microbiota, Food and Health.

[2] Bárcena, C., Valdés-Mas, R., Mayoral, P., Garabaya, C., Durand, S., Rodríguez, F., … & López-Otín, C. (2019). Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nature medicine, 25(8), 1234-1242.

Date Posted: February 12, 2021

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The Intertwined Nature of NAD+, CD38, and Senescence

Aging is a multifactorial and complex process; indeed, it is probably the most complex disorder known. It is made up of a combination of dozens of malfunctions locked together in an accelerating spiral of decline. Despite this undeniable complexity, which is captured to some extent by grouping the many age-related dysfunctions into nine categories often termed the “hallmarks of aging”, aspects of age-related molecular and cellular decline are often described and approached as distinct mechanisms [1].

Distinct mechanisms are difficult to reconcile with the substantial biological complexity of aging. Each “hallmark of aging” is comprised of processes that are undertaken by many networks of interacting proteins, and each network itself involves hundreds of protein species. Even at the organismal level, the Hallmarks are clearly not discrete entities but are themselves interconnected and overlapping. Trying to pick out single mechanisms embedded in the enormous cascade of complexity that underlies age-related decline might not be the most profitable approach imaginable.

This has been exemplified recently by the identification of links between three major manifestations of aging that have often been studied separately: NAD+ decline, cellular senescence, and chronic inflammation [2].

NAD+, cellular senescence and chronic inflammation

NAD+ is a ubiquitous molecule that plays a key role in multiple biological processes, ranging from energy metabolism to cell survival and repair. It is now known that cellular NAD+ levels decline with age and that this decline plays a direct role in the development of age-related metabolic dysfunction and disease [3]. Meanwhile, cellular senescence is a tumor-suppressive response that has evolved to prevent the unrestricted division of damaged and potentially cancerous cells.

Cellular Senescence

As your body ages, more of your cells become senescent. Senescent cells do not divide or support the tissues of which they are part; instead, they emit potentially harmful chemical signals, collectively known as the senescence-associated secretory phenotype (SASP), which encourages nearby cells to enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related ...
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Both restoration of NAD+ levels and the selective elimination of senescent cells independently promote health and extend lifespan in old or diseased animals [4, 5, 6]. Strategies to develop therapies to individually mitigate each of these hallmarks of aging are being developed.

Recent studies, however, have demonstrated that falling NAD+ levels and senescent cell recruitment are linked. This link appears to be mediated via another key hallmark of aging: chronic inflammation [1, 7].

Crosstalk between Hallmarks

It has recently been demonstrated that high NAD+ in cultured senescent cells increases their secretion of pro-inflammatory SASP cytokines due to inhibition of AMPK by high NAD+. This inhibition leads to downregulation of p53, activation of p38 MAPK, and upregulation of pro-inflammatory NF-kB [1].

This link between NAD+, senescence and inflammation deserves careful consideration. This observation is not evidence that high NAD+ causes senescence: in fact, NAD+ levels and senescence are strongly negatively correlated through life [8, 9, 10]. It is, however, evidence that NAD+ has a role in the biology of senescent cells, just as it has a role in all cells. Keeping in mind the complex, cascading nature of aging, is it also the case that senescence and the inflammatory SASP are drivers of age-related cellular NAD+ decline?

CD38 and chronic inflammation

Inflammatory SASP factors lead to increased expression of the cell membrane protein CD38 [7]. CD38 is found throughout the body with high expression on the surface of immune cells [11]. Its expression is robustly induced during immune cell activation, playing an important role in multiple aspects of the inflammatory response, including cell migration, activation, antigen presentation and cytokine release [12].

To perform its functions, CD38 consumes NAD+ in great quantities [13]. The accumulation of senescent cells with age leads to increased pro-inflammatory SASP. Increased SASP leads to spiraling levels of CD38 expression and a concurrent decrease in NAD+ levels [7].

Consistent with this effect of senescence on NAD+ levels, the expression and activity of CD38 increases during aging, paralleling the decrease in NAD+ levels [13, 14]. Aged wild-type mice have also been shown to have about half the NAD+ levels of young mice, whereas CD38 knockout mice maintain their NAD+ levels and are resistant to the negative effects of a high fat diet, including liver steatosis and glucose intolerance [15, 16]. Conversely, mice over-expressing CD38 have lower levels of NAD+, defective mitochondria, decreased oxygen consumption, and increased lactate production [14, 15].

The profound effect of CD38 on NAD+ levels is due to CD38 being an inefficient cyclase: CD38 must degrade nearly one hundred molecules of NAD+ to generate just one molecule of cADPR. CD38 is recognised as the primary NAD+ consumer in mammalian tissues [17].

Ultimately, this means that strategies to even slightly inhibit CD38 may lead to substantial increases in cellular NAD+ levels. In support of this, when CD38 is inhibited by flavonoids (e.g. luteolinidin, kuromanin, luteolin, quercetin and apigenin; IC50 <10 μM), a 50% increase in NAD+ is observed [16, 18]. Apigenin increases NAD+ levels in multiple tissues, decreasing global proteome acetylation and improving glucose and lipid homeostasis in obese mice, by increasing the activity of SIRT1 and SIRT3 [14, 16]. The CD38 inhibitor 78c has also been found to reverse age-related NAD+ decline and improve several physiological and metabolic parameters of aging, including glucose tolerance, muscle function, exercise capacity, and cardiac function in mouse models of natural and accelerated aging [19].

Resolving the NAD+ pro-inflammatory paradox

It is evident, therefore, that the relationship between these hallmarks of aging is complex. On one hand, NAD+ appears to facilitate the pro-inflammatory phenotype of senescent cells, while on the other hand, the pro-inflammatory SASP rather directly contributes to the demise of NAD+. The relationship between the two appears to be intertwined via chronic inflammation and CD38.

A key point is that the body is always in a dynamic equilibrium between different processes. Levels of biological molecules are not always good or always bad, they are beneficial or harmful depending on the current state of that equilibrium.

This is exemplified by senescent cells themselves. At first, senescent cells are beneficial to the body, as senescence lowers the risk of cancer. However, if these cells are not cleared away by the immune system, they begin to accumulate and the equilibrium shifts towards tissue damage, promoting inflammation and the further recruitment of senescent cells.

Similarly, in most circumstances, high NAD+ is beneficial, as demonstrated by a large number of studies that show that it promotes higher DNA repair, thus reducing DNA damage and senescence and generally robustifying cells, as is the case in youthful organisms [20, 21, 22, 23]. However, if the older body has already developed senescent cells, high NAD+ might reinforce their ability to secrete inflammatory factors.

With this in mind, some circumstances can be studied in which higher NAD+ might contribute to senescence-induced inflammation. However, the balance of risk is certain to lie the other way: if high NAD+ caused senescence-induced inflammation, then inflammation would reduce with age, as NAD+ does, but the reverse is true [24].

Other circumstances can be studied in which CD38 is suppressed while NAD+ levels are raised. In this circumstance, even if senescent cells are present in older tissues, the multiple benefits of restored NAD+, in increased DNA repair and cellular maintenance functions, for example, can be gained without powering up inflammatory processes [14, 16, 19].

Viewed at low resolution, it is possible to see parallels between the “generally good, but possibly sometimes less so” quality of restored NAD+ levels with the generality of oxygenated blood and nutrients being very beneficial – except when cancer is present, highlighting the danger of dissecting biological systems into their constituent parts without considering the wider context.

Conclusion

It is now evident that the hallmarks of aging are not discrete entities but are instead interconnected and interdependent networks. In light of this, strategies that try to address aging by focusing on isolated proteins, pathways or hallmarks are clearly not going to be enough. Even if we imagine that one process could be mitigated completely (100% amelioration of the accumulation of senescent cells, for example), all the other elements of the cascade would proceed to their unfortunate conclusion.

If we’re going to stop or reverse aging, we’re going to have to look at the deep-rooted causes of aging and understand the complex interplay between them. If the goal is to affect aging beneficially, tackling only one thing will almost always be insufficiently effective. Instead, several factors must be addressed at once, targeting not just one hallmark but simultaneously targeting a substantial proportion of the cascading network of age-related decline.

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Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194–1217. https://doi.org/10.1016/j.cell.2013.05.039

[2] Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., Aird, K. M., Iwasaki, O., Kossenkov, A. V., Schultz, D., Noma, K. I., Baur, J. A., Schug, Z., Tang, H. Y., Speicher, D. W., David, G., & Zhang, R. (2019). NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nature cell biology, 21(3), 397–407. https://doi.org/10.1038/s41556-019-0287-4

[3] Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell metabolism, 27(3), 529–547. https://doi.org/10.1016/j.cmet.2018.02.011

[4] Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D’Amico, D., Ropelle, E. R., Lutolf, M. P., Aebersold, R., Schoonjans, K., Menzies, K. J., & Auwerx, J. (2016). NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science (New York, N.Y.), 352(6292), 1436–1443. https://doi.org/10.1126/science.aaf2693

[5] Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., Redpath, P., Migaud, M. E., Apte, R. S., Uchida, K., Yoshino, J., & Imai, S. I. (2016). Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell metabolism, 24(6), 795–806. https://doi.org/10.1016/j.cmet.2016.09.013

[6] van Deursen J. M. (2019). Senolytic therapies for healthy longevity. Science (New York, N.Y.), 364(6441), 636–637. https://doi.org/10.1126/science.aaw1299

[7] Chini, C., Hogan, K. A., Warner, G. M., Tarragó, M. G., Peclat, T. R., Tchkonia, T., Kirkland, J. L., & Chini, E. (2019). The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline. Biochemical and biophysical research communications, 513(2), 486–493. https://doi.org/10.1016/j.bbrc.2019.03.199

[8] van der Veer, E., Ho, C., O’Neil, C., Barbosa, N., Scott, R., Cregan, S. P., & Pickering, J. G. (2007). Extension of human cell lifespan by nicotinamide phosphoribosyltransferase. The Journal of biological chemistry, 282(15), 10841–10845. https://doi.org/10.1074/jbc.C700018200

[9] Borradaile, N. M., & Pickering, J. G. (2009). Nicotinamide phosphoribosyltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environment. Aging cell, 8(2), 100–112. https://doi.org/10.1111/j.1474-9726.2009.00453.x

[10] Jadeja, R. N., Powell, F. L., Jones, M. A., Fuller, J., Joseph, E., Thounaojam, M. C., Bartoli, M., & Martin, P. M. (2018). Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence. Aging, 10(6), 1306–1323. https://doi.org/10.18632/aging.101469

[11] Piedra-Quintero, Z. L., Wilson, Z., Nava, P., & Guerau-de-Arellano, M. (2020). CD38: An Immunomodulatory Molecule in Inflammation and Autoimmunity. Frontiers in immunology, 11, 597959. https://doi.org/10.3389/fimmu.2020.597959

[12] Amici, S. A., Young, N. A., Narvaez-Miranda, J., Jablonski, K. A., Arcos, J., Rosas, L., Papenfuss, T. L., Torrelles, J. B., Jarjour, W. N., & Guerau-de-Arellano, M. (2018). CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions. Frontiers in immunology, 9, 1593. https://doi.org/10.3389/fimmu.2018.01593

[13] Aksoy, P., White, T. A., Thompson, M., & Chini, E. N. (2006). Regulation of intracellular levels of NAD: a novel role for CD38. Biochemical and biophysical research communications, 345(4), 1386–1392. https://doi.org/10.1016/j.bbrc.2006.05.042

[14] Camacho-Pereira, J., Tarragó, M. G., Chini, C., Nin, V., Escande, C., Warner, G. M., Puranik, A. S., Schoon, R. A., Reid, J. M., Galina, A., & Chini, E. N. (2016). CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell metabolism, 23(6), 1127–1139. https://doi.org/10.1016/j.cmet.2016.05.006

[15] Barbosa, M. T., Soares, S. M., Novak, C. M., Sinclair, D., Levine, J. A., Aksoy, P., & Chini, E. N. (2007). The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 21(13), 3629–3639. https://doi.org/10.1096/fj.07-8290com

[16] Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa, M. T., O’Neil, L., White, T. A., Sinclair, D. A., & 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. https://doi.org/10.2337/db12-1139

[17] Chini, C., Tarragó, M. G., & Chini, E. N. (2017). NAD and the aging process: Role in life, death and everything in between. Molecular and cellular endocrinology, 455, 62–74. https://doi.org/10.1016/j.mce.2016.11.003

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[22] Fang, E. F., Kassahun, H., Croteau, D. L., Scheibye-Knudsen, M., Marosi, K., Lu, H., Shamanna, R. A., Kalyanasundaram, S., Bollineni, R. C., Wilson, M. A., Iser, W. B., Wollman, B. N., Morevati, M., Li, J., Kerr, J. S., Lu, Q., Waltz, T. B., Tian, J., Sinclair, D. A., Mattson, M. P., … Bohr, V. A. (2016). NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. Cell metabolism, 24(4), 566–581. https://doi.org/10.1016/j.cmet.2016.09.004

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[24] Franceschi, C., & Campisi, J. (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The journals of gerontology. Series A, Biological sciences and medical sciences, 69 Suppl 1, S4–S9. https://doi.org/10.1093/gerona/glu057

Date Posted: February 11, 2021

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Male and Female Gut Microbiomes Converge With Age

While the gut microbiomes of young men and women are distinct, that difference disappears in older people, according to a new study. These findings add to the growing pool of data that links the gut microbiome and aging, although the nature of the links and the mechanisms behind them remain questions for future research.

The gut microbiome has been linked with many aspects of our biology, from immune response regulation to involvement in disorders such as diabetes. Studies in a variety of animals have reported sex-linked differences in the gut microbiome, but the findings have been somewhat inconsistent, perhaps because of the influence of other factors, such as diet and environment. These inconsistencies led a team of researchers at Chinese institutes to investigate how the gut microbiomes of a population in Beijing varied with sex, sex hormones, age, and a range of metabolic and clinical metrics.

The researchers sequenced the microbiomes of 2,338 adults aged 26-76 in Beijing and correlated this data with 88 parameters measured through lab tests and questionnaires. They found that it was possible to distinguish the gut microbiomes of men and women aged 26-50, but in individuals older than 50, this difference disappeared. The researchers were able to validate these findings in an independent cohort from China and another from the Netherlands, but not in an Israeli cohort.

The age-related changes in the microbiome didn’t correlate with sex, diet, or the lifestyle or metabolic parameters measured in the study. In other words, it seems that the microbiome probably changes as a result of age-related physiological changes rather than alterations of diet or lifestyle. Characterizing these changes and understanding how they work could offer insights into what happens during aging or at least tools to probe this particular aspect further.

The team tried to use their findings to establish a “microbiome clock” – an estimator of age based on microbiome data – but they found that it performed well in some cohorts but poorly in others.

Unlike Horvath’s methylation clock that accurately reflects the rate of host intrinsic aging at the molecular level, the gut microbiota-based age-prediction models based on a combined set of age-associated microbial features at both the individual and population levels seem to be less universally applicable.

Abstract

Lifelong sex- and age-related trajectories of the human gut microbiota remain largely unexplored. Using metagenomics, we derived the gut microbial composition of 2,338 adults (26–76 years) from a Han Chinese population-based cohort where metabolic health, hormone levels and aspects of their lifestyles were also recorded. In this cohort, and in three independent cohorts distributed across China, Israel and the Netherlands, we observed sex differences in the gut microbial composition and a shared age-related decrease in sex-dependent differences in gut microbiota. Compared to men, the gut microbiota of premenopausal women exhibited higher microbial diversity and higher abundances of multiple species known to have beneficial effects on host metabolism. We also found consistent sex-independent, age-related gut microbial characteristics across all populations, with the presence of members of the oral microbiota being the strongest indicator of older chronological age. Our findings highlight the existence of sex- and age-related trajectories in the human gut microbiota that are shared between populations of different ethnicities and emphasize the pivotal links between sex hormones, gut microbiota and host metabolism.

Conclusion

This isn’t the first study to investigate the link between the gut microbiome and aging, and it almost certainly won’t be the last. This study represents an extensive analysis of a well-defined cohort, together with validation in other cohorts, resulting in a wealth of data about the trajectory of the gut microbiome. The paper also digs into the effect of sex hormones: testosterone is associated with microbiome diversity, while estrogen isn’t linked, but this doesn’t seem to be connected with the difference between sexes. It’s not clear if or how changes in sex hormones are linked with the disappearance of distinct sex-based microbiomes with age. The complex interplay between sex hormones, age-related physiology, the gut microbiome, and other aspects of aging will doubtless provide fodder for years of research.

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Literature

[1] Zhang X, Zhong H, Li Y, Shi Z, Ren H, Zhang Z, Zhou X, Tang S, Han X, Lin Y, Yang F, Wang D, Fang C, Fu Z, Wang L, Zhu S, Hou Y, Xu X, Yang H, Wang J, Kristiansen K, Li J, and Ji L. Sex- and age-related trajectories of the adult human gut microbiota shared across populations of different ethnicities. Nature Aging (2021), doi: 10.1038/s43587-020-00014-2

[2] Özkurt E and Hildebrand F. Lifelong sex-dependent trajectories of the human gut microbiota. Nature Aging (2021), doi: 10.1038/s43587-020-00019-x

Date Posted: February 10, 2021

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Lessons from Longevity Therapeutics 2021 – Part 3

The Third Annual Longevity Therapeutics Summit brought together some of the biggest names translating longevity research into human patients. This is part three of our coverage of this conference; you can find part one here and part two here, and the final installment will be published shortly.

Brian Culley – Lineage Cell Therapeutics

Lineage Cell Therapeutics is a company that works on cell transplantation as a treatment for various age-related diseases. While most companies in this space are focused on stem cells, Lineage uses fully differentiated cells for its treatments. These cells have already been “pushed” towards a specific cell type. Afterwards, the cells cannot differentiate into other cell types. These cells replicate less readily, but their behaviors are more predictable. Lineage is working on applying its technology to target dry age-related macular degeneration with retinal cells, spinal cord injuries with oligodendrocytes, and non-small cell lung cancer with dendritic cells. The company has seen good results thus far in the 24 patients enrolled in its phase 1/2a study for macular degeneration, especially when the intervention was conducted at an early stage. The company also plans to announce data from a similarly sized study in spinal cord injury soon and is currently enrolling cancer patients to receive its novel dendritic cell treatment. Lineage also has made some impressive innovations in manufacturing cell-based products – a notoriously troublesome area in the field of cell therapy.

Dr. Marc Ramis-Castelltort – Rejuveron

Rejuveron is a platform company that funds and supports start-ups that take aim at aging and longevity. Its portfolio companies include Endogena, which utilizes small molecules to facilitate tissue regeneration, RejuverVas, which aims to reduce age-related brain decline by increasing its vascularization, and the newly formed RejuverSen. RejuverSen, which is led by Dr. Ramis-Castelltort, develops therapies for the immune-mediated clearance of senescent cells. Senescent cells are often left behind in cancer treatments and have been shown to contribute to cancer recurrence. Senescent cells also escape immune clearance through a newly discovered mechanism, which RejuverSen intends to utilize for its therapies. The team has also been recently profiling human tumors to help shape their therapeutic strategy. If successful, Dr. Ramis-Castelltort believes that this same concept can be used to eliminate senescent cells in other age-related pathologies.

Colin Watts – JuvLife

Juvenescence, another longevity-based platform company, has been very active in the world of dietary supplements recently with the launch of JuvLife and BHB Therapeutics. This company aims to develop proprietary supplements to increase healthspan in a high-quality, science-based manner. The company has four products in development (with a three-year “bench to market” timetable) and plans to expand to twelve. Mr. Watts hinted that the first, a ketone ester that mimics aspects of the ketogenic diet, fasting, and strenuous exercise, may be available soon. He also presented an inside look at the company’s target consumers and early adopters for its products, having identified through surveys what it refers to as “lifetime optimizers.” These are individuals with a number of positive characteristics led by a strong drive to make the most out of their lives.

Dr. Scott Shandler – Longevity Biotech

Longevity Biotech currently has preclinical programs in neuroinflammation, diabetes, and oncology. Dr. Shandler presented on his company’s clinical stage program for Parkinson’s disease. There is an inverse relationship between neurodegeneration and cancer. In neurodegeneration, misfolded proteins cause a disproportionate pro-inflammatory response, which contributes to the pathology. Simply suppressing the immune system may not be the best strategy. Instead, Longevity Biotech is looking to rebalance the pro-inflammatory versus anti-inflammatory response. In its first clinical study, the company is looking for biomarkers that will identify patients with Parkinson’s who also have immune dysfunction. Unlike more common approaches that immediately attempt to test a therapeutic in a diseased population, this precision medicine strategy will hopefully help determine “responders” and “non-responders” ahead of time to improve the likelihood of successful treatments.

Dr. Marco Quarta – Rubedo

This was the second time we heard from Dr. Quarta, as he gave an excellent opening talk the previous day. Rubedo is targeting natural aging and chemotherapy survivors with its drug design platform. This company has developed the technology to create prodrugs, which are inactive until metabolized by the body, making them more stable and less toxic than their non-prodrug counterparts but just as effective. Reducing side effects will be critical to the success of longevity treatments, as such treatments are more preventative in nature than traditional drugs, which often treat more immediately life-threatening conditions. Rubedo’s lead candidate clears senescent cells, improves physical function, and improves cognition in mouse models of chemotherapy, neurodegeneration, and natural aging. The company is in the midst of lead optimization for idiopathic pulmonary fibrosis (IPF) and COPD, and it is looking to start IND enabling studies (an FDA requirement to begin clinical trials) this year. Rubedo also has preclinical stage programs for cancer, neuro-musculo-skeletal problems, and fibrosis of the liver and kidney.

If you would like to know more, cou can read about the other days below:

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Date Posted: February 9, 2021

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Lessons from Longevity Therapeutics 2021 – Part 2

We continue our coverage of Longevity Therapeutics 2021 and bring you part 2 of day 1.

Dr. Steven Braithwhite – Chief Scientific Officer, Alkahest

Steven Braithwhite from Alkahest gave an update on the company’s ongoing clinical trials. Alkahest has been sifting plasma proteome in search for proteins that decrease or increase with age. The company calls such proteins chronokines and targets them with its candidate drugs, which are based, in part, on precisely formulated plasma fractions. Alkahest has been testing its candidates against Alzheimer’s disease, Parkinson’s disease, and age-related macular degeneration (AMD), and the company is currently running several parallel Stage 2 clinical trials.

Preliminary data presented at the conference appears promising. One of Alkahest’s candidate drugs, GRF6019, was able to stall cognitive decline in several dozen patients with mild to moderate AD over the course of six months, showing a marked improvement over the control group. Another candidate, AKST4290, caused a significant reduction in peripheral and central inflammation in a preclinical mouse model. Alkahest’s work is an example of the recent focus on blood plasma among longevity scientists; we have been reporting on Drs. Irina and Michael Conboy’s groundbreaking research in the field, and check out our interview with a team of Russian biohackers who decided to take matters into their own hands and conduct a plasma dilution experiment on themselves.

Dr. Aubrey de Grey – Founder & Chief Scientific Officer, SENS Research Foundation

Aubrey de Grey needs no introduction. In his wide-ranging talk, he reiterated the basics of longevity research, including the seven types of damage that aging inflicts on our bodies. He also briefly touched on some relatively recent successes, such as the synthesis of glucosepane in 2015, and listed several spin-off companies that SENS has launched. One of them, Revel Pharmaceuticals, is working on enzymes that break glucosepane crosslinks (read our interview with Alexander Fedintsev on why extracellular matrix stiffening, caused in large part by glucosepane crosslinks, might be considered a new hallmark of aging). According to Dr. de Grey, there are currently well over a hundred startups in aging research. However, commercially speaking, the field is still in its infancy, which creates well-known problems, such as extreme price volatility of public longevity companies being triggered by even minor setbacks. De Grey called on fellow scientists to increase their involvement by “becoming worldwide thought leaders” and by making bolder predictions in relation to specific timeframes – something that scientists are usually averse to doing. De Grey asserted that this is the only way to “reassure the investor herd that profits are coming.” He ended his talk with musing that the COVID-19 pandemic might ultimately save more lives than it has claimed if, as a result, the world starts taking age-related diseases more seriously.

Reenie McCarthy – Chief Executive Officer, Stealth BioTherapeutics

Reenie McCarthy from Stealth BioTherapeutics gave a fascinating talk on mitochondrial decline as a cause of multiple age-related disorders, and her company has been making steady progress in this field. Just last month, it was granted a pre-NDA (new drug application) meeting for Elamipretide, its main candidate drug, as a treatment for Barth syndrome, a rare condition characterized by an enlarged and weakened heart. Age-related mitochondrial dysfunction hits the most energy-demanding systems in our body the hardest. These include the eyes, the heart, and the brain. Mitochondria comprise as much as 35% of the volume of cardiomyocytes, cells entrusted with heart contraction, and there are hundreds to thousands of mitochondria in every neuron. Elamipretide apparently normalizes mitochondrial morphology by reducing the production of toxic reactive oxygen species (ROS). Four other Elampretide trials, targeting ophthalmic and neurological disorders, are currently in Stage 2.

Dr. Alex Zhavoronkov – Founder & Chief Executive Officer, Insilico

Not many companies are as emblematic of the AI revolution in longevity research as Insilico Medicine. Alex Zhavoronkov described in depth the company’s end-to-end approach, which consists of three consecutive stages. One platform, called PandaOMICS, searches for perspective therapeutic targets by analyzing -omics data, such as genomic and proteomic. Another platform, Chemistry42, explores the vast chemical realm looking for molecules that can potentially influence these targets of interest. Finally, a third platform, InClinico, designs clinical trials and predicts their outcomes. The company has had its greatest success with Chemistry42, which is the fastest existing drug discovery platform, according to MIT’s Top 10 Breakthroughs of 2020. Several big pharma companies, including Pfizer and Merck, have already established drug discovery partnerships with Insilico. Meanwhile, the company’s research arm has turned its attention towards the link between cellular senescence and fibrosis. According to Zhavoronkov, the buildup of cellular senescence increases fibrosis, which, in turn, increases senescence, a phenomenon that he suggested should be called either senofibrosis or fibrosenescence. These two facets of biological aging also share many pathways. Without divulging many details, Zhavoronkov claimed a success on this front and promised a major announcement as soon as later this month.

Dr. Ronjon Nag – Founder, R42 institute

As AI and machine learning were a recurrent theme at the conference, it was reasonable for the organizers to arrange a workshop on AI and longevity. The workshop was led by Dr. Ronjon Nag, who is currently at Stanford and the founder of the R42 Institute that helps emerging companies, including in the longevity field, to integrate AI in their work. Dr. Nag began with a short introduction to AI, the turbulent history of AI research in which troughs followed crests more than once, and its basic tools. Nag then listed several medical applications where AI already shines, including personalized treatments, AI-powered gadgets that are helping to tilt the balance towards prevention, and the creation of more robust biomarkers of aging. Nag also mentioned what is probably the most spectacular success of AI in recent years: AlphaFold’s solving of the protein folding problem. AI is rapidly becoming an indispensable tool in medical research, and scientists need assistance and education in this field. Nag gave a brief overview of the current projects that attempt to do just that, such as MD.ai.

If you would like to know more, cou can read about the other days below:

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Date Posted: February 8, 2021

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Senescent Cells in the Aging Retina

A review published in the Journal of Neuroinflammation explores the potential application of senotherapies, particularly in the context of treating age-related macular degeneration [1].

Introducing cellular senescence

One of the most advanced approaches to treating aging and age-related diseases is that of addressing the presence of harmful senescent cells, which begin to accumulate with advancing age as the immune system and other clearance methods begin to break down. Worse still, the pace of this accumulation speeds up as we get older, creating a downward spiral.

Cellular Senescence

Suggested solutions to this problem include destroying the cells using senolytics, modifying the SASP to be less harmful using senomorphics, slowing down the rate of senescent cell accumulation via cell cycle regulation, using cell therapies or drugs to rejuvenate the immune system so that it quickly removes senescent cells, and, more recently, rescuing senescent cells from their harmful state and returning them to homeostasis. Collectively, these different approaches are known as senotherapies.

The senolytic strategy is currently the most popular, as destroying and removing the problematic cells is the most practical and direct approach. Certainly, in animal studies involving aged mice, senolytic treatment to clear senescent cells appears to spur rejuvenation, as it reduces inflammaging, the chronic systemic inflammation that accompanies aging, and reverses a number of aging biomarkers.

Focusing on age-related macular degeneration

The presence and importance of senescent cells in the eyes during aging, particularly in the development of AMD, is becoming increasingly clear. As we established earlier, cell senescence is an key driver of age-related diseases, including AMD, and the authors of this review do a good job of diving into the mechanisms behind cellular senescence and what causes a cell to enter this harmful state, including telomere attrition, DNA damage, excessive exposure to reactive oxygen species, and loss of metabolic homeostasis.

One of the more interesting parts of the review includes a Venn diagram of three kinds of senescent cells in the eye and the various elements of the SASP that each type secretes. Three components, interleukin 12, interleukin 6, and tumor necrosis factor alpha, are produced by all three of the types.

A Venn diagram of the SASP produced by three types of senescent cells.

This really serves to highlight the fact that there is considerable variation between populations of senescent cells, and we have discussed the heterogeneity of senescent cells in previous articles. This is why the project being undertaken by a team of researchers, including professor Judith Campisi, to build an atlas of senescent cells is so important.

The authors go on to explore how the different senescent cell types in the eye contribute to the progression of AMD and the complex interplay between them. There is also particular emphasis on the role of senescent immune cells. The review goes on to discuss the various adaptive metabolic pathways through which cellular senescence supports the progression of AMD and the signaling cascades that it triggers.

The final part of the review considers the potential of senotherapies in the context of addressing AMD.

Age-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed “chronic” senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

Conclusion

Age-related macular degeneration and a wide range of age-related diseases could potentially be ameroliated by senotherapies. Right now, there are several companies developing senotherapies poised to enter human trials this year; UNITY Biotechnology is already in trials for diabetic macular edema, another age-related visual condition supported by senescent cells, with its senolytic candidate UBX1325.

UBX1325 is also being evaluated for its potential to treat other age-related diseases of the eye, including age-related macular degeneration and proliferative diabetic retinopathy. We anticipate that initial data from this trial could be announced later this year, and we are keeping our fingers crossed that the results will be positive for UNITY this time.

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Literature

[1] Lee, K. S., Lin, S., Copland, D. A., Dick, A. D., & Liu, J. (2021). Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration. Journal of Neuroinflammation, 18(1), 1-17.

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Replacing Aging With Jean Hébert

Lessons from Longevity Therapeutics 2021 – Part 4

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