$200m Biotech SPAC includes David Sinclair | Lifespan Research Institute

Date Posted: March 12, 2021

David Sinclair and Peter Attia Co-chair $200m Biotech SPAC

Another special purpose acquisition company (SPAC) focused on longevity and rejuvenation biotechnology has appeared recently, and with the addition of research rockstars David Sinclair and Peter Attia, it could mean a bright future for healthy longevity.

We recently talked about how SPACs could transform the longevity research industry in Humacyte in Deal to Develop Prosthetic Vasculature, and now a second company has taken the SPAC route to market.

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.

The SPAC deal could potentially make it easier for Frontier Acquisition Corporation 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 Frontier Acquisition Corporation

Frontier Acquisition Corporation recently announced the pricing of its initial public offering of 20,000,000 units at a price of $10.00 per unit. The units are listed on the Nasdaq Capital Market and will trade under the ticker symbol FRONU.

The SPAC is led by Chief Executive Officer Christian Angermayer, Co-Presidents Rick Gerson and Ryan Khoury, and Co-Chairmen of the board David Sinclair, Peter Attia and director Jonathan Christodoro. The SPAC is certain to have a strong focus on longevity and companies developing ways to increase healthy human lifespan, given the board members.

For a start, Christian Angermayer, the founder of Apeiron Investment Group and Chairman and Co-Founder of Cambrian Biopharma, is leading the SPAC, and his views on healthy longevity are very clear.

In an article published on Linkedin Pulse, he stated, “And gradually, it will go further than just money. I believe we will finally see AGING and DYING officially recognised for what they are: a collection of diseases that can be prevented, cured and reversed.” He goes on to openly state his desire for increased healthy longevity thanks to science: “Put simply, I want to live forever! And in perfect health! And it is my sincere belief that we will achieve the means to do this within the next 20-30 years.”

The SPAC stated in its recent press release that it “intends to pursue opportunities at the intersection of the healthcare and technology industries” but that it “will not be limited to a particular industry or geographic region in its identification and acquisition of a target company.”

Focusing on increasing healthy longevity

Perhaps the most interesting news here is the inclusion of David Sinclair and Peter Attia, two big names in the aging research and longevity field.

David Sinclair, Professor of Genetics at Harvard Medical School, is perhaps best known for his research on nicotinamide adenine dinucleotide (NAD+) and the NAD+ precursor molecule nicotinamide mononucleotide (NMN).

David Sinclair and his team successfully launched the NAD+ Mouse Project with us here on lifespan.io in 2018 to find out if NMN could increase healthy longevity in mice. That experiment is still currently in progress at Harvard Medical School, and we hope to bring you some news on progress later this year.

David Sinclair has also co-founded a number of biotechnology companies, including being a board member of Life Biosciences, a company and several daughter companies that all collectively work to address the nine hallmarks of aging. He is also the author of the excellent book “Lifespan – Why we age and why we don’t have to“.

Peter Attia is a practising physician who focuses on the practical application of scientific knowledge to support healthy longevity with the tools we have easily available today. As such, much of his focus is upon lifestyle, exercise, diet, sleep, and fasting as ways to maximize health and decelerate aging as much as possible. This is a sensible strategy given that technologies to increase healthy longevity could start to arrive in the next decade or two, so it’s best to stay alive in good health until then.

He hosts the Peter Attia Drive Podcast, a weekly podcast that focuses on maximizing longevity while taking into account the physical, cognitive, and emotional aspects of health. Peter Attia is also the Chief Medical Officer of the fasting app Zero, an app designed to make fasting for longevity and health purposes both safer and easier.

Conclusion

The creation of another SPAC focused on acquiring promising biotech companies working on targeting aging for increased healthy longevity is an exciting prospect. The fact that more and more money is flowing into the field really shows the sea change that has happened in the last four or five years. It seems that there is now a daily stream of biotech firms that focus on aging and increased longevity, which represents a stark contrast to how things were only half a decade ago.

Aging research, rejuvenation biotechnology, and longevity tech are no longer fringe fields: they are small but growing research fields that are primed to potentially become the largest industry in history. With multiple human trials poised to begin this year and some already in progress, just a single success against human aging will likely open the floodgates for even greater funding to flow into the field. We anticipate that we will be seeing more and more SPACs focused on healthy longevity in the next year or two.

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Date Posted: March 11, 2021

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Managing Stress Responses to Slow Down Aging

Longevity research should better incorporate the effects of stress on aging, argues professor Elissa Epel of the University of California, San Francisco [1]. She proposes using the concept of stress resilience to capture the differences between beneficial and harmful stress and the multi-level response that mediates the link between stress and aging.

Different types of stress

Epel praises the shift from what she calls the whack-a-mole approach of trying to cure specific diseases to an integrative approach that tries to understand and address biological aging as the underlying cause of these diseases. However, she advocates incorporating stress responses more fully into this model, viewing them as basic mechanisms of aging rather than modifiers.

Her approach includes both physiological stressors that are already part of longevity research, such as hypoxia, and psychological stressors that have received less attention, such as divorce, loss of a job, and caregiving. Epel highlights the importance of interactions between the two types, such as poor mental health affecting recovery from physical stress; she offers the example that depression increases the risk of slow recovery and early mortality in heart disease patients. To some extent, this reflects the fact that stress mediates the link between the social hallmarks and aging.

The paper also discusses the familiar division between chronic stress, which is toxic, and acute stress, which can be beneficial, a process known as hormesis. Epel writes that the cellular biology of hormesis is relatively well characterized, but she wants to expand the concept to include psychological stressors such as “novel challenging experiences that expand coping resources, knowledge, generativity, and feelings of accomplishment.”

Resilience to stress

Epel wants to combine these disparate elements into the concept of stress resilience: the ability of an individual to recover quickly from stressful exposures. She frames the idea to include resilience in three dimensions: physiological, psychological, and social. A person’s ability to cope with stress – and thus its impact on aging – is determined not only by biological stress response but also by that person’s personality, support networks, and related resources.

“Stress resilience, an umbrella term including hormetic stress, can be measured across cellular, physiological, and psychosocial functioning,” said Epel in a press release. “Developing a deeper understanding of stress resilience will lead to more targeted innovative interventions.”

Introducing the concept of stress resilience opens the door to new questions for longevity researchers. For example, how does stress resilience change during development? Aging leads to a decrease in the hormones involved in acute stress response and a decrease in hormesis. The psychological and social dimensions of stress resilience probably also change, which may shift the value of different interventions.

Boosting our capacity

Another benefit is that resilience can serve as a target for interventions. Taking Epel’s view that stress is a basic mechanism of aging, an argument can be made that there is an ideal stress level for longevity. Too much stress leads to accelerated aging, while too little results in the failure to develop buffering resources to cope with stress and an inability to quickly recover.

Stress resilience determines the range of these domains and the size of the Goldilocks zone that results in enhanced functioning, which Epel calls ‘stress rejuvenescence’. Increased stress resilience can help ensure that stress has a beneficial impact on longevity instead of accelerating aging. Interventions that increase our capacity to cope with stress – including social and psychological tools that are already available – could have a significant impact and increase both health- and lifespan.

Geroscience offers a counterpoint to the challenged pursuit of curing diseases of aging, by focusing on slowing the biological aging process for extended healthspan earlier in life. Remarkable progress has led this field toward animal trials and the next challenge lies with translation to humans. There is an emerging number of small human trials that can take advantage of new models integrating behavioral and social factors. Understanding dynamic aging mechanisms, given the powerful social determinants of aging (Crimmins, 2020) and human variability and environmental contexts (Moffitt, 2020), will be critical. Behavioral and social factors are intrinsic to aging. Toxic stressors broadly defined can lead to stress-acceleration of aging, either directly impacting aging processes or by shaping poor behavioral health, and underlie the socioeconomic disparities of aging. In contrast, hormetic stressors, acute intermittent stressors of moderate intensity, can produce stress resilience, the ability for quick recovery and possibly rejuvenation of cells and tissues. Although health research usually examines static biomarkers, aging is reflected in dynamic ability to recover from challenges pointing to new interventions and targets for examining mechanisms. A fuller model incorporating stress resilience provides innovative biobehavioral interventions, both for bolstering response to challenges, such as COVID-19, and for improving healthspan.

Conclusion

Epel’s paper offers a coherent framework for integrating various aspects of stress and stress response into longevity research. She argues that in addition to considering ways to reduce stress, especially chronic stress, scientists should aim to increase stress resilience, as building up this capacity will improve our ability to cope with stress without detrimental aging effects. As Epel wrote in the paper, “models which are focused on pharmacological interventions must expand to be inclusive of both social and behavioral interventions, the current ‘big levers.'”

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Literature

[1] Epel, ES. The geroscience agenda: Toxic stress, hormetic stress, and the rate of aging. Ageing Research Reviews (2020), doi: 10.1016/j.arr.2020.101167

Date Posted: March 10, 2021

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A Summary of NAD+ and Human Aging – Part 2

Welcome to part two of a two-part series exploring NAD+ biology; you can find part one here. There are already a myriad of excellent reviews on NAD+ biology in general [1-3], so, in this article, we will be mainly focusing on the NAD+ precursor nicotinamide mononucleotide (NMN).

NMN and synthesis of NAD+

NMN can be readily found in low amounts in a wide variety of foods, such as fruit, vegetables, and meat, but it is only recently that its potential has been investigated in animal models.

NMN is produced from nicotinamide (NAM), a form of water-soluble vitamin B3, and 50-phosphoribosyl-1-pyrophosphate (PRPP) by nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD+ biosynthetic enzyme found in mammals. NMN is also created from nicotinamide riboside (NR) via a phosphorylation reaction mediated by nicotinamide riboside kinase (NRK).

The conversion of NMN into NAD+ is facilitated by nicotinamide mononucleotide adenylyltransfereases (NMNATs), rate-limiting enzymes that are present in all organisms. Data from rodent studies has shown that NMN can increase NAD+ biosynthesis in multiple tissues, including the pancreas, liver, adipose tissue, heart, skeletal muscle, kidneys, eyes, and blood vessels [4-15].

It is still not totally clear if NMN can cross the blood-brain barrier (BBB), as it may be too large to pass through the membrane from the bloodstream into the brain. However, studies show that intraperitoneal injection increases NAD+ in multiple brain regions, including the hippocampus and hypothalamus, within 15 minutes of administration [16-17]. This strongly suggests that NMN can pass through the BBB and increase NAD+ synthesis in the brain.

NAD+ and the implications for therapies against age-related diseases

A year-long study of wild-type C57BL/6 mice showed that NMN is tolerated well [18]. The mice were given up to 300 mg/kg during the study and suffered no adverse reactions or toxic effects. This suggests that NMN has therapeutic potential, and there is a growing amount of research that shows it has beneficial effects on a varied range of physiological functions, meaning that it may have broad implications as a therapy for treating age-related diseases.

So far, there have been several observed benefits of NMN administration. Some studies suggest that beta cells in the pancreas are sensitive to changes in NAD+ levels and to NMN treatment. A single injection of NMN at a dose of 500 mg/kg in mice increases glucose-stimulated insulin production, thereby improving glucose tolerance in age- and diet-induced diabetic mice [19-20]. This also improved the situation in NAMPT knockout mice and in aged wild-type and beta cell-specific SIRT1-overexpressing mice [21-23].

Data also suggests that NMN improves the activity of insulin along with its production. Mouse studies show that treatment with NMN improves hepatic insulin resistance induced by a high-fat diet by restoring NAD+ synthesis, increasing the activity of SIRT1, a critical signaling molecule that interacts with NAD, and reducing gene expressions associated with oxidative stress, inflammation and circadian rhythms [24].

Other studies show that long-term NMN consumption suppresses age-related inflammation in adipose tissue and improves whole-body insulin sensitivity in normally aging wild-type C57BL/6 mice [25]. NAD+ synthesis is impaired in obese and aged mice, so this study suggests that adipose tissue NAD+ could be a suitable target for insulin resistance, key risk factors for type 2 diabetes, and cardiovascular disease.

The administration of NMN has also been shown to improve the function of mitochondria in multiple organs and tissues. Mice treated with NMN have been found to have increased mitochondrial oxidative phosphorylation in skeletal muscle tissue; this likely helps with weight control by increasing whole-body energy expenditure during normal day-to-day function and movement [26]. This also leads to the improvement of skeletal muscle mitochondrial oxidative metabolism and endothelial function along with reversal of vascular aging in mice [27-29]. NMN also appears to address retinal degeneration via interaction with the mitochondrial sirtuins SIRT3 and SIRT5, at least in NAMPT knockout mice [30].

In terms of the brain, NMN appears to improve various neuronal functions, with administration improving both cognition and memory in mouse and rat models of Alzheimer’s disease [31-33]. NMN also appears to have neuroprotective properties and protects neurons from death following ischemia or intracerebral hemorrhage [34-35]. NMN also reduces the age-related loss of neural stem cells in the dentate gyrus of wild-type C57BL/6 mice [36].

Moving to the kidneys, NMN appears to inhibit acute renal injury via a SIRT1-mediated response [37]. NMN has also been shown to improve DNA damage repair from radiation [38].

More research is needed

While it is clear that NMN has beneficial effects in multiple tissues and organs in rodents; indeed, there are various conditions that show significant loss of NAD+ levels, there are also a number of unknown things about NAD+ that should be resolved.

For example, it is still unclear what downstream mechanisms are mediating the beneficial effects of improved NAD+ synthesis. NAD+ is involved in the activity of poly ADP ribose polymerases (PARPs), sirtuins, ADPribosyl cyclases, and mono-ADP ribosyltransferases while serving as a cofactor in redox reactions for a myriad of enzymes.

On one hand, we know that the inhibition or deletion of sirtuins blocks the positive benefits of NAD+ repletion, which spotlights the key role these enzymes have in working in unison with NAD+ [39]. On the other hand, the inhibition of NAD+ consuming enzymes, such as PARP1/2 and CD38, give similar benefits to increasing NAD+ via therapeutically increasing it [40-43].

Given the complex interactions at play here, it will take a considerable research effort to discern what exactly is going on, how these various benefits are conveyed, and the exact downstream mechanisms at play here. As part of that process, it is also critical to carefully assess any potential negative side effects of NAD+ therapies, particularly their intermediates.

While little evidence to date suggests that increasing NAD+ promotes cancer development, there are concerns that boosting NAD+ may help already established tumors to grow [44], especially given the recent finding that NAD+ boosting increases the development of the vascular system by facilitating SIRT1-mediated crosstalk between endothelial cells and muscle tissue [45]. SIRT1 has been shown to have both pro and anticarcinogenic effects in a context-dependent manner [46]. So far, there is no observed increased cancer incidence in mice, but it is something to consider for the future development of therapies that increase cellular NAD+.

Conclusion

The results of mouse studies suggest that NAD+ repletion approaches hold great potential, but as always in science, we should be cautious. Thus, further preclinical and clinical studies are needed to establish the long-term safety of NMN as a human therapeutic.

Fortunately, there are currently ongoing human trials for NMN being conducted with a view to establishing toxicity and safety profiles over the long term, so we should have data in due course that will inform us of where to go next.

Literature

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[2] Fang, E. F., Lautrup, S., Hou, Y., Demarest, T. G., Croteau, D. L., Mattson, M. P., & Bohr, V. A. (2017). NAD+ in aging: molecular mechanisms and translational implications. Trends in molecular medicine.

[3] Imai, S. I., & Guarente, L. (2014). NAD+ and sirtuins in aging and disease. Trends in cell biology, 24(8), 464-471.

[4] Yoshino, J., Mills, K. F., Yoon, M. J., & Imai, S. I. (2011). Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet-and age-induced diabetes in mice. Cell metabolism, 14(4), 528-536.

[5] Peek, C. B., Affinati, A. H., Ramsey, K. M., Kuo, H. Y., Yu, W., Sena, L. A., … & Levine, D. C. (2013). Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science, 342(6158), 1243417.

[6] Stromsdorfer, K. L., Yamaguchi, S., Yoon, M. J., Moseley, A. C., Franczyk, M. P., Kelly, S. C., … & Yoshino, J. (2016). NAMPT-mediated NAD+ biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell reports, 16(7), 1851-1860.

[7] Karamanlidis, G., Lee, C. F., Garcia-Menendez, L., Kolwicz, S. C., Suthammarak, W., Gong, G., … & Tian, R. (2013). Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell metabolism, 18(2), 239-250.

[8] Martin, A. S., Abraham, D. M., Hershberger, K. A., Bhatt, D. P., Mao, L., Cui, H., … & Locasale, J. W. (2017). Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model. JCI insight, 2(14).

[9] North, B. J., Rosenberg, M. A., Jeganathan, K. B., Hafner, A. V., Michan, S., Dai, J., … & Van Deursen, J. M. (2014). SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. The EMBO journal, e201386907.

[10] Yamamoto, T., Byun, J., Zhai, P., Ikeda, Y., Oka, S., & Sadoshima, J. (2014). Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. PloS one, 9(6), e98972.

[11] Gomes, A. P., Price, N. L., Ling, A. J., Moslehi, J. J., Montgomery, M. K., Rajman, L., … & Mercken, E. M. (2013). Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155(7), 1624-1638.

[12] Guan, Y., Wang, S. R., Huang, X. Z., Xie, Q. H., Xu, Y. Y., Shang, D., & Hao, C. M. (2017). Nicotinamide Mononucleotide, an NAD+ Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1–Dependent Manner. Journal of the American Society of Nephrology, ASN-2016040385.

[13] Lin, J. B., Kubota, S., Ban, N., Yoshida, M., Santeford, A., Sene, A., … & Yoshino, J. (2016). NAMPT-mediated NAD+ biosynthesis is essential for vision in mice. Cell reports, 17(1), 69-85.

[14] Picciotto, N. E., Gano, L. B., Johnson, L. C., Martens, C. R., Sindler, A. L., Mills, K. F., … & Seals, D. R. (2016). Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell, 15(3), 522-530.

[15] Sinclair D. Bonkowski, M. Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging (2018) doi.org/10.1016/j.cell.2018.02.008

[16] Stein, L. R., & Imai, S. I. (2014). Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging. The EMBO journal, 33(12), 1321-1340.

[17] Yoon, M. J., Yoshida, M., Johnson, S., Takikawa, A., Usui, I., Tobe, K., … & Imai, S. I. (2015). SIRT1-mediated eNAMPT secretion from adipose tissue regulates hypothalamic NAD+ and function in mice. Cell metabolism, 21(5), 706-717.

[18] Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., … & Yoshino, J. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell metabolism, 24(6), 795-806.

[19] Caton, P. W., Kieswich, J., Yaqoob, M. M., Holness, M. J., & Sugden, M. C. (2011). Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function. Diabetologia, 54(12), 3083-3092.

[20] Yoshino, J., Mills, K. F., Yoon, M. J., & Imai, S. I. (2011). Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet-and age-induced diabetes in mice. Cell metabolism, 14(4), 528-536.

[21] Revollo, J. R., Körner, A., Mills, K. F., Satoh, A., Wang, T., Garten, A., … & Milbrandt, J. (2007). Nampt/PBEF/visfatin regulates insulin secretion in β cells as a systemic NAD biosynthetic enzyme. Cell metabolism, 6(5), 363-375.

[22] Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., … & Yoshino, J. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell metabolism, 24(6), 795-806.

[23] Ramsey, K. M., Mills, K. F., Satoh, A., & Imai, S. I. (2008). Age‐associated loss of Sirt1‐mediated enhancement of glucose‐stimulated insulin secretion in beta cell‐specific Sirt1‐overexpressing (BESTO) mice. Aging cell, 7(1), 78-88.

[24] Yoshino, J., Mills, K. F., Yoon, M. J., & Imai, S. I. (2011). Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet-and age-induced diabetes in mice. Cell metabolism, 14(4), 528-536.

[25] Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., … & Yoshino, J. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell metabolism, 24(6), 795-806.

[26] Gomes, A. P., Price, N. L., Ling, A. J., Moslehi, J. J., Montgomery, M. K., Rajman, L., … & Mercken, E. M. (2013). Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155(7), 1624-1638.

[27] Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., … & Yoshino, J. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell metabolism, 24(6), 795-806.

[28] Picciotto, N. E., Gano, L. B., Johnson, L. C., Martens, C. R., Sindler, A. L., Mills, K. F., … & Seals, D. R. (2016). Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell, 15(3), 522-530.

[29] Sinclair D. Bonkowski, M. Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging (2018) doi.org/10.1016/j.cell.2018.02.008

[30] Lin, J. B., Kubota, S., Ban, N., Yoshida, M., Santeford, A., Sene, A., … & Yoshino, J. (2016). NAMPT-mediated NAD+ biosynthesis is essential for vision in mice. Cell reports, 17(1), 69-85.

[31] Wang, X., Hu, X., Yang, Y., Takata, T., & Sakurai, T. (2016). Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain research, 1643, 1-9.

[32] Long, A. N., Owens, K., Schlappal, A. E., Kristian, T., Fishman, P. S., & Schuh, R. A. (2015). Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model. BMC neurology, 15(1), 19.

[33] Yao, Z., Yang, W., Gao, Z., & Jia, P. (2017). Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neuroscience letters, 647, 133-140.

[34] Wei, C. C., Kong, Y. Y., Li, G. Q., Guan, Y. F., Wang, P., & Miao, C. Y. (2017). Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway. Scientific reports, 7(1), 717.

[35] Park, J. H., Long, A., Owens, K., & Kristian, T. (2016). Nicotinamide mononucleotide inhibits post-ischemic NAD+ degradation and dramatically ameliorates brain damage following global cerebral ischemia. Neurobiology of disease, 95, 102-110.

[36] Stein, L. R., & Imai, S. I. (2014). Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging. The EMBO journal, 33(12), 1321-1340.

[37] Guan, Y., Wang, S. R., Huang, X. Z., Xie, Q. H., Xu, Y. Y., Shang, D., & Hao, C. M. (2017). Nicotinamide Mononucleotide, an NAD+ Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1–Dependent Manner. Journal of the American Society of Nephrology, ASN-2016040385.

[38] Li, J., Bonkowski, M. S., Moniot, S., Zhang, D., Hubbard, B. P., Ling, A. J., … & Aravind, L. (2017). A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science, 355(6331), 1312-1317.

[39] Brown, K. D., Maqsood, S., Huang, J. Y., Pan, Y., Harkcom, W., Li, W., … & Jaffrey, S. R. (2014). Activation of SIRT3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell metabolism, 20(6), 1059-1068.

[40] Bai, P., Canto, C., Brunyánszki, A., Huber, A., Szántó, M., Cen, Y., … & Gergely, P. (2011). PARP-2 regulates SIRT1 expression and whole-body energy expenditure. Cell metabolism, 13(4), 450-460.

[41] Bai, P., Cantó, C., Oudart, H., Brunyánszki, A., Cen, Y., Thomas, C., … & Schoonjans, K. (2011). PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell metabolism, 13(4), 461-468.

[42] Camacho-Pereira, J., Tarragó, M. G., Chini, C. C., Nin, V., Escande, C., Warner, G. M., … & Chini, E. N. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell metabolism, 23(6), 1127-1139. [43] Schultz, M. B., & Sinclair, D. A. (2016). Why NAD+ declines during aging: It’s destroyed. Cell metabolism, 23(6), 965-966.

[44] Gujar, A. D., Le, S., Mao, D. D., Dadey, D. Y., Turski, A., Sasaki, Y., … & Rich, K. M. (2016). An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma. Proceedings of the National Academy of Sciences, 113(51), E8247-E8256.

[45] Sinclair D. Bonkowski, M. Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging (2018) doi.org/10.1016/j.cell.2018.02.008

[46] Chalkiadaki, A., & Guarente, L. (2015). The multifaceted functions of sirtuins in cancer. Nature Reviews Cancer, 15(10), 608.

Date Posted: March 10, 2021

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Longevity Pharmacology with Dr. João Pedro de Magalhães

Dr. João Pedro de Magalhães is a Professor at the University of Liverpool, England, where he studies aging and longevity at the genetic level, and he is also an affiliate Principal Investigator in the Neuroendocrinology and Aging Group at the University of Coimbra, Portugal. Dr. de Magalhães has built the Human Ageing Genomic Resources (HAGR), a curated database of genes related to aging. He recently published an article on the subject of life-extending drugs.

We took the opportunity to interview him on his article along with his thoughts about the current state and future trajectory of life extension research.

João, first off, I really loved your most recent article published in Drug Discovery Today. It was great to read a birds-eye-view take on the longevity field from someone who has been on its forefront for so long. What was your motivation for writing the piece?

Thank you, I am really glad you liked my recent article.

Back in September 2020, I did a talk at the Aging Research and Drug Discovery meeting and played with some of the data in our GenAge and DrugAge databases on genes and drugs associated with aging and longevity. I noticed that the number of drugs associated with aging has been increasing exponentially, while the number of genes has sort of plateaued. I mentioned this in my talk, and I thought it would be a nice basis for an article as well. Then we also did some analysis of investment and companies working in longevity, which confirmed my suspicions that there is a growing investment in the area. So, I thought this would be a really nice topic for a brief article, highlighting the growth in the longevity biotech industry.

One of my main takeaways from the article was that there are reasons for cautious optimism in the field. Is that a fair representation of your views? And, if so, what are the biggest reasons why we should be optimistic? What approaches are you most excited about?

Yes, I am cautiously optimistic about the development of longevity drugs in particular, what I call in my article “longevity pharmacology”. I think the discovery that aging and longevity can be manipulated in animals has really changed the field; we have seen a rapid and significant growth in the study of aging. And there are a number of companies now starting to focus on longevity. So, I think there is a sense of energy in the field that I find very interesting and positive. Keep in mind, of course, that most of these companies and approaches will fail, but if only one of them succeeds, that will be groundbreaking.

Do you think your level of optimism now has been increasing, decreasing, or holding steady over the years? And if it has changed, why?

My optimism regarding developing interventions in aging has increased, again because of the manipulations of aging in animal models, and the growing number of longevity drugs and companies in the anti-aging biotech industry. So compared to 20 years ago when I started working in aging, nowadays, aging is a proper field of study; it is an established branch of science. Aging and longevity are still small when compared to other fields, like cancer or Alzheimer’s disease, but aging is picking up pace and growing in excitement, people, and funding.

Of course, the future is uncertain, and there are reasons for pessimism too. For example, you mention that many biotech companies are focused on translating only a few of the possible strategies that have emerged, and we could benefit from a more diverse set of approaches. What do you see as some of the other main bottlenecks to the longevity field?

I think the crucial bottleneck in the longevity field is the time it takes to do experiments. And really there is no way around it, no matter how much money and how much technology we have, you still need to do longevity and aging studies, at least in animal models. And that remains as the main bottleneck of research: the fact that we need to do long, time-consuming experiments to test any intervention or gene for aging.

We have another issue I think as well in that we don’t fully understand the process of aging. In fact, I don’t think we understand the causes of human aging yet. There are a number of hypotheses and pathways that we know about, but in humans, none are proven; perhaps human aging is actually different from what everybody is focusing on. Hence why I say we need to be more creative.

In the piece, you mention the TAME trial. Do you think this will represent a paradigm shift for the field? Will other studies start to follow their model or could it potentially be more of a one-off?

I am very excited about the TAME trial, I think it will be a wonderful proof of concept for developing clinical trials for aging. Even if the trial itself is a failure, it will be a tremendous learning experience for the field, and it will pave the way for future similar studies. My guess would be that we will learn a lot of lessons on how to conduct such studies from the TAME trial, even if most likely some tweaking will be necessary in the future. Science is a gradual process; you go step-by-step improving and learning. And the TAME trial is a great step in the right direction but not the final destination.

Along similar lines, the NIA announced last week that it will be funding clinical trials targeting aging. Of course, the FDA still requires an approval to be disease-specific, but we haven’t seen a funding announcement like this from the NIA before. On a scale from business-as-usual to we should be celebrating in the streets, how big of a deal is this?

I don’t know the background to the announcement, but I take it as a very positive sign that the field as a whole is becoming more translational; indeed, this is one of the points I make in my recent article. Again, it’s a long journey, and we need to take it step by step, but this is another step in the right direction.

I also want to ask about what’s next for you and your lab. Can you give us a little tease about what you are most excited about that we should be on the lookout for in the near future?

We have several different projects that I’m excited about. We are looking into single cell sequencing in the context of aging, which is a very interesting approach to untangle cell interactions, and potentially even tissue interactions in the context of aging. I think this is a very underexplored topic in aging. We’re also doing some work on long-lived species, for example in this very recent study. We also have some results coming out soon on the interactions between aging and cancer using multi-omics (see here for a quick preview). We also recently got funding to develop a new project that I’m very excited about: we aim to apply machine learning to discovery and predict drug combinations that retard aging.

Lastly, in addition to my university lab, I am also now CSO of Centaura, an ambitious Swiss-based company. We are developing new gene and cell therapies with multiple applications, including in aging.

Thanks so much for taking the time for this interview! Finally, where can our readers follow you if they want to learn more and stay up to date on your work?

Please follow me on Twitter, and I’m also on LinkedIn.

We would like to thank Dr. Magalhães for taking the time to speak to us about the field and about his work with longevity pharmacology.

Date Posted: March 9, 2021

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Binary Clock Predicts Biological Age

Scientists have devised a transcriptome-based aging clock that allows for precise measurement of biological age in C. elegans worms and shows promising results in humans as well [1].

The purpose of aging clocks

One of the central questions of longevity research is how to measure biological age. If a pathology, genetic difference, lifestyle choice, or treatment either shortens or prolongs life, it affects your biological age. It’s crucial to be able to accurately measure this because human lifespan is so long: if we couldn’t measure alterations in lifespan without waiting for people to die, human trials of anti-aging interventions would take decades.

Theoretically, an aging clock could use any set of parameters that correlate with aging; it just has to correctly predict the effect of lifespan-altering events. Recently, methylation clocks have been steadily gaining in popularity, as DNA methylation controls gene expression by changing the shape of our chromatin: a methylated site (one that has a methyl group added to it) coils and stops being transcribed. Although the expression of certain genes can go up or down as we age, methylation levels generally decline with time [2], which means that more transcription is going on, including harmful transcription of sites that are normally silenced, such as retrotransposons [3].

Introducing binarization

Methylation is not the only factor that affects transcription; if transcription is what matters, an aging clock based on transcription levels rather than simple methylation is theoretically superior. Also, not all model organisms in longevity research modulate their transcription the way we do. C. elegans nematode worms are an extremely popular subject of aging research, for various reasons, but they mostly lack DNA methylation [4].

In this new paper, the researchers describe building an aging clock based on a set of 576 genes whose expression correlates with aging in C. elegans. After determining the set of genes, an AI model was trained on 900 worm transcriptomes obtained during various other studies, and then they tested it on another 100.

This was not the first attempt to create a transcriptomic clock for C. elegans, but this time, the researchers introduced an alteration that proved crucial: they binarized the levels of transcription. In this process, they assigned only one of two possible values to the transcription level of each gene, depending on whether it is above or below average. By doing so, the researchers were able to discard a lot of noise, and they claim that the resulting binary transcriptomic (BiT) model is more robust and approaches the theoretical maximum accuracy for C. elegans lifespan.

High prediction power

The researchers were able to correctly predict the lifespan-altering effects of certain genetic variations, environmental factors, and interventions, including caloric restriction, metformin supplementation, extreme heat, and harmful bacteria. The aging clock was stress-tested in various scenarios, such as the combined effect of more than one drug (some drugs cancel the life-prolonging effect of rapamycin, while others amplify it, and the model successfully predicted effects of such cocktails). The model accounted for such subtle effects as the duration of treatment and the genetic variance of the worms’ E. coli food supply. At times, the model was able to predict the future effect of a factor that had occurred on the first day of the worms’ lives.

The model was also successfully tested on different unrelated datasets with other lifespan-affecting stressors to show that there was no overfitting. Overfitting, one of the fundamental problems in machine learning, is when the model learns the quirks of its training dataset and makes spectacular predictions on similar datasets but fails on all others.

Human results

The researchers then applied the same method to human transcriptomes, using a different set of genes but retaining the principle of binarization. The resulting model shows superior predictive power over similar, non-binarized models – for instance, it successfully predicted the greatly increased biological age of children suffering from progeria, a genetic disease that accelerates aging.

Conclusion

If the results of this study can be successfully reproduced, it may show that the researchers have struck gold with their binarization approach that successfully removes noise from transcriptomic data. Longevity research is in dire need of reliable aging clocks, and this binary aging clock may be an improvement over existing methylation-based clocks.

Literature

[1] Meyer, D. H., & Schumacher, B. (2021). BiT age: A transcriptome‐based aging clock near the theoretical limit of accuracy. Aging Cell, e13320.

[2] Johnson, A. A., Akman, K., Calimport, S. R., Wuttke, D., Stolzing, A., & De Magalhaes, J. P. (2012). The role of DNA methylation in aging, rejuvenation, and age-related disease. Rejuvenation research, 15(5), 483-494.

[3] Mahmood, W., Erichsen, L., Ott, P., Schulz, W. A., Fischer, J. C., Arauzo-Bravo, M. J., … & Santourlidis, S. (2020). Aging-associated distinctive DNA methylation changes of LINE-1 retrotransposons in pure cell-free DNA from human blood. Scientific reports, 10(1), 1-12.

[4] Weinhouse, C., Truong, L., Meyer, J. N., & Allard, P. (2018). Caenorhabditis elegans as an emerging model system in environmental epigenetics. Environmental and molecular mutagenesis, 59(7), 560-575.

Date Posted: March 8, 2021

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Video Gaming as a Geroprotective Strategy

Contrary to certain sensationalist articles declaring that video games are harmful, there is, in fact, growing evidence that playing video games may have a positive effect on cognitive health, particularly in older people [1].

Today, we will be taking a look at the scientific evidence to see if brain training or hitting your favorite video game titles could help keep you healthy as you age.

Could playing video games be a useful part of a health and longevity strategy?

Studies have already shown that video game training can improve a number of cognitive functions, including memory, reaction time, cognitive control, attention span, and the ability to multitask, including in young adults [2-6].

The data suggests that complex, three-dimensional video games may improve hippocampal-associated memory, which is performed by the part of the brain responsible for the storage and recall of declarative memories [7]. Declarative memory is the memory of facts and events and refers to memories that can be consciously recalled (or declared).

Scientific studies also suggest that playing video games may improve posture, balance, and muscle strength [8-10]. This is particularly relevant for older adults who are at greater risk of falls and resulting injuries while generally helping to combat sarcopenia and the frailty it brings.

Online gaming takes things a step further

With the prevalence of online video games, we see a fusion of mental, physical, and social aspects [11]. Players all over the world share online worlds together, participate in group activities, such as battles and quests, and compete with each other in contests of skill. These games go beyond the simple entertainment concepts of video games and explore many vistas of human experience.

The meteoric rise of eSports in recent years has seen a shift away from video gaming simply being for personal entertainment, and it is now watched by millions worldwide in the same way as traditional sports, such as football, baseball and so on [12]. Video games such as Starcraft 2, Overwatch, League of Legends, Dota 2, and CS:GO have a dedicated eSports network, with rosters of professional and semi-professional teams competing in leagues for cash and prizes, just as traditional sports games have. eSports involve a complex network of social, physical and mental interactions that previous video game culture did not encompass [13]. It might be useful to study the long-term effects of being an eSports player and its impact on health.

Massive multiplayer online games (MMOs), such as World of Warcraft, Guild Wars 2, Neverwinter, Elder Scrolls online, and Eve Online, are also very popular and bring together many social aspects as well as the regular physical and mental ones that video gaming demands. The players of these games inhabit persistent online worlds that evolve and change as players interact with them, and they encompass a microcosm of social conventions, economies, and shared experiences.

Online communities are communities of practice

These games are essentially communities of practice where players compete and cooperate in a manner that goes way beyond simple gaming for entertainment [14-15]. A community of practice is formed by people who engage in a process of collective learning in a shared environment, such as a tribe learning to survive, scientists working on a shared problem such as aging, a group of doctors sharing novel techniques, company managers sharing best practices, and, of course, online video gaming communities learning and developing new skills and strategies.

Given that socializing is well documented as being an important key to aging and longevity, one has to wonder what impact such social gaming might have on aging [16-17]. We know that socializing via social media versus physical socializing is markedly different in terms of the response it produces in the brain, with direct physical interaction being much more beneficial and protective against the effects of social isolation [18-22]. However, social media is fairly static and nowhere near as dynamic as these online gaming communities are, so perhaps future studies will map these social interactions and their effects on the brain and compare them with face-to-face socializing.

Another aspect of exposure to these communities of practice is that an older player has the opportunity to learn and develop new skill sets as part of regular interactions. Not so long ago, video games were traditionally considered the domain of the young, but with the aging of the original video gaming generations born in the 1970s and 1980s, it is common to encounter middle-aged or older players on a frequent basis in online games today.

These older players can benefit from these communities of practice just the same as younger ones, and they may develop skills and cognitive abilities that they could also find useful in life outside gaming, such as problem-solving and teamwork abilities that could be potentially applied to real-world situations [23].

Conclusion

So, perhaps picking up your controller and playing the latest video game title, or even better joining your friends for some online gaming could be a helpful longevity measure; just make sure you mix it with physical activity and take plenty of breaks while gaming to avoid being sedentary.

Finally, perhaps the best of both worlds is the rising popularity of virtual reality (VR) gaming, and while the cost of the equipment is still relatively high, that situation is likely to improve as technology and manufacturing processes improve. VR games have the advantages of cognition-stimulating video games combined with the physical movement and activity associated with sports or exercise. Games such as Beat Saber, a sound and rhythm game taking place in a surrealistic neon environment that features the player slicing blocks representing musical beats with a pair of contrasting-colored sabers, can help work up a sweat and is also great fun. There are increasing number of VR games appearing on the market, so it could be worth considering if you are looking to combine gaming and physical activity.

While there is no substitute for direct social interaction, video gaming does appear to have a number of aspects in its favor, especially in relation to cognitive ability. As games and the methods of interaction evolve through new technologies such as virtual reality, there may be even more opportunities to collectively socialize, learn, and interact, further enhancing the benefits of being part of communities of practice.

Literature

[1] De Schutter, B., & Abeele, V. V. (2015). Towards a gerontoludic manifesto. Anthropology & Aging, 36(2), 112-120.

[2] Nouchi, R., Taki, Y., Takeuchi, H., Hashizume, H., Akitsuki, Y., Shigemune, Y., … & Kawashima, R. (2012). Brain training game improves executive functions and processing speed in the elderly: a randomized controlled trial. PloS one, 7(1), e29676.

[3] Nouchi, R., Taki, Y., Takeuchi, H., Hashizume, H., Nozawa, T., Kambara, T., … & Kawashima, R. (2013). Brain training game boosts executive functions, working memory and processing speed in the young adults: a randomized controlled trial. PloS one, 8(2), e55518.

[4] Toril, P., Reales, J. M., & Ballesteros, S. (2014). Video game training enhances cognition of older adults: a meta-analytic study. Psychology and aging, 29(3), 706.

[5] Anguera, J. A., Boccanfuso, J., Rintoul, J. L., Al-Hashimi, O., Faraji, F., Janowich, J., … & Gazzaley, A. (2013). Video game training enhances cognitive control in older adults. Nature, 501(7465), 97.

[6] Dye, M. W., Green, C. S., & Bavelier, D. (2009). Increasing speed of processing with action video games. Current directions in psychological science, 18(6), 321-326.

[7] Clemenson, G. D., & Stark, C. E. (2015). Virtual environmental enrichment through video games improves hippocampal-associated memory. Journal of Neuroscience, 35(49), 16116-16125.

[8] Lee, Y., Choi, W., Lee, K., Song, C., & Lee, S. (2017). Virtual reality training with three-dimensional video games improves postural balance and lower extremity strength in community-dwelling older adults. Journal of aging and physical activity, 25(4), 621-627.

[9] Ray, N. R., O’Connell, M. A., Nashiro, K., Smith, E. T., Qin, S., & Basak, C. (2017). Evaluating the relationship between white matter integrity, cognition, and varieties of video game learning. Restorative neurology and neuroscience, 35(5), 437-456.

[10] Lamoth, C. J., Caljouw, S. R., & Postema, K. (2011). Active video gaming to improve balance in the elderly.

[11] Narme, P. (2016). Benefits of game-based leisure activities in normal aging and dementia. Geriatrie et psychologie neuropsychiatrie du vieillissement, 14(4), 420-428.

[12] Hamari, J., & Sjöblom, M. (2017). What is eSports and why do people watch it?. Internet research, 27(2), 211-232.

[13] Seo, Y., & Jung, S. U. (2016). Beyond solitary play in computer games: The social practices of eSports. Journal of Consumer Culture, 16(3), 635-655.

[14] Wenger-Trayner, E., & Wenger-Trayner, B. (2015). Introduction to communities of practice: A brief overview of the concept and its uses. Grass Valley, CA: Wenger-Trayner.

[15] Ybarra, O., Burnstein, E., Winkielman, P., Keller, M. C., Manis, M., Chan, E., & Rodriguez, J. (2008). Mental exercising through simple socializing: Social interaction promotes general cognitive functioning. Personality and Social Psychology Bulletin, 34(2), 248-259.

[16] Gilmour, H. (2012). Social participation and the health and well-being of Canadian seniors. Health reports, 23(4), 1B.

[17] Holt-Lunstad, J., Smith, T. B., Baker, M., Harris, T., & Stephenson, D. (2015). Loneliness and social isolation as risk factors for mortality: a meta-analytic review. Perspectives on Psychological Science, 10(2), 227-237.

[18] Redcay, E., Dodell-Feder, D., Pearrow, M. J., Mavros, P. L., Kleiner, M., Gabrieli, J. D., & Saxe, R. (2010). Live face-to-face interaction during fMRI: a new tool for social cognitive neuroscience. Neuroimage, 50(4), 1639-1647.

[19] Grippo, A. J., Trahanas, D. M., Zimmerman, R. R., Porges, S. W., & Carter, C. S. (2009). Oxytocin protects against negative behavioral and autonomic consequences of long-term social isolation. Psychoneuroendocrinology, 34(10), 1542-1553.

[20] Saphire-Bernstein, S., Way, B. M., Kim, H. S., Sherman, D. K., & Taylor, S. E. (2011). Oxytocin receptor gene (OXTR) is related to psychological resources. Proceedings of the National Academy of Sciences, 108(37), 15118-15122.

[21] Rice, K., Moraczewski, D., & Redcay, E. (2016). Perceived live interaction modulates the developing social brain. Social cognitive and affective neuroscience, 11(9), 1354-1362.

[22] Rice, K., & Redcay, E. (2016). Interaction matters: A perceived social partner alters the neural processing of human speech. NeuroImage, 129, 480-488.

[23] Grossman, A. (2013). Postmortems from Game Developer: Insights from the Developers of Unreal Tournament, Black & White, Age of Empire, and Other Top-Selling Games. Focal Press.

Date Posted: March 8, 2021

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Maximon Launches Longevity Biotech Builder

We kick off the week with some news from Switzerland and introduce the new longevity biotech company builder Maximon.

The enthusiasm for technologies to promote longevity and even increase healthy human lifespan seems to be rising in Switzerland. There are frequently articles in the popular press about the topic and we were even asked to write an article for Schweizer Monat (Swiss Month) in February 2020 called “The ways to longevity“, which took a look at the near-future longevity tech that could change how we age.

We include the official press release below and let it do most of the talking, but in a nutshell, Maximon is a Switzerland-based biotech incubator that aims to identify and develop promising biotech companies that focus on creating therapies that target the aging processes and thus increase healthy longevity through the delaying, prevention, or even reversal of age-related diseases.

There are now a number of longevity company builders around the world, all of which approach things in a slightly different way. The arrival of Maximon is most welcome and they appear to be taking a more hands-on approach to building the actual companies from the ground up.

The more companies focused on developing technologies and therapies to support healthy longevity, the better; quite simply, the more rejuvenation startups there are, the greater the chances that one of them will succeed in the near future and show the world that human aging is not a one-way street and that we may have a choice regarding how we age in the next few decades.

Maximon launches the world’s first longevity company builder
Zug/Switzerland, March 8th, 2021 – Maximon is the new company builder based in Switzerland with the aim to extend the health-span and to allow humans to reach a fit, healthy and happy longevity.
Maximon will start several companies per year and provide a comprehensive set of resources that empowers founders to focus on and create superior services and products and execute at speed on a global scale. The resulting company cluster is highly synergetic and allows Maximon to impact the longevity sector from multiple angles simultaneously. Maximon plans to allocate CHF 50million+ over the next 4 years and to raise a larger longevity focused fund thereafter.
“Longevity will be one of the largest, if not the largest, investment opportunities in the decades to come. At Maximon, we want to monetize this huge business opportunity by empowering entrepreneurs to build impactful, science-based and scalable companies that investigate and perpetuate healthy aging and rejuvenation solutions”, says Founding Partner Dr. Tobias Reichmuth. “The recent progress in science relating to life and health extension is very impressive and creates unique and massive business opportunities”, adds the Founding Partner Marc P. Bernegger.
The founding team is complemented by serial entrepreneur and investor Jörg Rieker, venture building expert Caroline Faisst, and three additional team-members.
Maximon is supported by a scientific advisory board consisting of Prof. Dr. Collin Ewald from ETH Zurich and Prof. Dr. Evelyne Yeudit Bischof, MD, MPH from Shanghai University of Medicine and Health Sciences and Human Longevity Inc., by industry advisors like Adrian Locher (Co-Founder of DeinDeal and Merantix) and Alexander Thiel (Partner and Lead Consumer Goods Practice at McKinsey & Company).
Dr. Tobias Reichmuth and Marc P. Bernegger are also the initiators of the “Longevity Investors Conference”, which targets the global investor community.
About Maximon
Maximon is a longevity company builder based in Switzerland with the mission to become the leading player in the field of longevity and healthy lifespan by empowering entrepreneurs to build impactful, science-based and scalable companies, which provide healthy aging and rejuvenation solutions.More information about Maximon can be found on www.maximon.com
About Longevity
Longevity is the science of anti-aging research and rejuvenation and has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes. Longevity identifies both lifestyle and pharmaceutical targets to improve the human health-span (i.e. the time we can live without any negative impact from aging).
Contact
Maximon Ltd.
Bahnhofplatz
CH-6300 Zug
Switzerland
Email: contact@maximon.com

Date Posted: March 4, 2021

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The Social Hallmarks of Aging

A professor at the University of Southern California has proposed that longevity researchers expand their toolkit to include social hallmarks of aging [1]. This paper is one of a trio that offer a fresh perspective on geroscience by trying to integrate findings from a biological approach into the complex dynamics of humans as social animals.

A framework for longevity research

In a 2013 Cell paper [2], researchers at several European research institutes proposed a list of nine hallmarks of aging. The perspective provided by the hallmarks helped bring together different strands of longevity research into a coherent, interconnected framework which could guide further research in the field. While researchers have proposed expanding or completely revising the list of hallmarks [3], the underlying goal continues to be to approach aging as a set of intertwined molecular and cellular changes.

This paradigm has helped longevity researchers make remarkable progress. While more work is needed to deepen our understanding of the hallmarks and their interactions, scientists have already identified potential genetic, nutritional, and pharmacological longevity interventions, and several human trials are underway. However, the time has come to expand the Hallmarks framework to include social determinants of aging, argues University of Southern California professor and AARP Chair in Gerontology, Eileen Crimmins.

Getting social

Crimmins explains that the social hallmarks aren’t just a vague reference to social factors influencing aging. Crimmins analysed data from the Health and Retirement Study, a large, nationally representative study of Americans over 56, and showed that social metrics were strong predictors of aging, even when biological factors were accounted for. Here is how she explained it in a press release:

Variability in human aging is strongly related to the social determinants of aging, and it remains so when extensive biology is introduced as mediating factors. This means that the social variability in the aging process is only partly explained by the biological measures researchers currently use.

Crimmins focused on five social hallmarks: socioeconomic status, adverse childhood experiences, adult trauma, negative psychological states, and poor health behaviors such as smoking and drinking. Her models included these along with demographic factors (age and sex) and biological metrics such as telomere length, epigenetic age, and the difference between biological and chronological age. She built models with different combinations of these factors to predict multimorbidity, disability, cognitive deficiency, and two-year mortality.

In the model that included social and biological factors, she found that social factors contributed much more than biological factors to the variance in all of the outcomes. In other words, social factors explained most of the difference in aging in this study population. This is a striking finding given that most current longevity research focuses on biological causes and interventions. (The paper is open access; readers interested in more details can have a look at her precise findings.)

Bringing it together

Crimmins notes that a full biological understanding of aging would presumably preclude the need to consider its social determinants.

Our hypothesis is that if we could fully capture the basic biological mechanisms of aging, they would even more strongly explain the social variability in the process of aging, as social factors need to ‘get under the skin’ through biology.

A complete biological picture of aging remains beyond the horizon for the moment. In the meantime, incorporating the social hallmarks into longevity research can not only guide us towards undiscovered biological aging processes but also provide actionable interventions to alleviate the social causes of aging. In the conclusion of her paper, Crimmins wrote:

“We have far to go before we are able to include indicators of all of the hallmarks of biological aging into human population studies, but these initial measures are somewhat disappointing. The evidence presented suggests that focus on the social hallmarks of aging will help to achieve the geroscience agenda to slow human aging.”

Abstract

This paper focuses on the social hallmarks of aging including low lifetime socioeconomic status, adversity in childhood and adulthood, being a member of a minority group, adverse health behaviors, and adverse psychological states. The “Social Hallmarks of Aging” are analogous to the “Geroscience Hallmarks of Aging” in reflecting a set of underlying and interrelated social causes of multiple age-related health outcomes. The paper presents empirical work incorporating the social hallmarks of aging with indicators of multiple biological hallmarks of aging as well as downstream biology in explaining a range of health outcomes. Results show the relative strength of the associations of social and biological measures with important health outcomes. Social factors are strongly related to physical and cognitive functioning and multimorbidity in this older population; this remains true when the significant number of biological measures are controlled. These results can be interpreted to mean that a significant amount of the social variance in age-related health outcomes is not explained by these measures of biology. Indicators of the geroscience hallmarks of aging only relate modestly to the variability in human health outcomes. Attention to the social hallmarks related to human aging can usefully be incorporated into work on the biological hallmarks of aging to make greater progress in understanding human aging.

Conclusion

Adding the social hallmarks to our longevity toolkit is an excellent idea. It broadens our framework for understanding how humans age and also highlights things that we can do now to address it. While we wait for – and work towards – interventions that could increase our maximum lifespan, there are many choices we can make now to increase median lifespan and healthspan. Social organizations and structures that alleviate the pressures identified in the social hallmarks would improve the lives, health, and lifespan of many people. It would also demonstrate the benefit of longevity research in highlighting and addressing these links, which will help convince people of its value and reinforce that the goal is longevity for the many, not the few.

Yes I will donate❤️

Literature

[1] Crimmins EM. Social hallmarks of aging: Suggestions for geroscience research. Ageing Research Reviews (2020), doi: 10.1016/j.arr.2020.101136

[2] López-Otín C, Blasco MA, Partridge L, Serrano M, and Kroemer G. The hallmarks of aging. Cell (2013), doi: 10.1016/j.cell.2013.05.039.

[3] Franceschi C, Garagnani P, Parini P, Giuliani C, and Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. (2018), doi: 10.1038/s41574-018-0059-4.

Date Posted: March 4, 2021

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Kizoo Provides Seed Funding for Elastrin Therapeutics

Rejuvenation biotechnology startup founder Kizoo has provided Elastrin, a company that focuses on removing calcification from tissue, with seed funding.

The company Elastrin is named for elastin, which comprises the fibers affected by this calcification. The company is using a proprietary antibody to deliver a nanoparticle-encased therapeutic agent directly to the fibers in question. The company hopes to use this approach to treat arterial tissues, as calcification of the arteries leads to hardening of the arteries and its associated downstream effects, such as aneurysms and hypertension.

Calcification is not the only source of degraded arterial function, as advanced glycation end-products such as glucosepane are also known to play a role through stiffening of the collagen. However, Elastrin’s approach, if successful, may ameliorate many age-related cardiovascular diseases and potentially reduce the risk of stroke and heart attack.

Kizoo is part of the Forever Healthy Foundation, an organization that funds research against aging and sponsors the annual Undoing Aging conference.

Here is the full press release:
Kizoo provides seed funding for Elastrin Therapeuticsto develop groundbreaking new technology capable of reversing tissue and organ calcification
Clemson SC, USA / Berlin, Germany
Elastrin is a biotechnology startup leveraging a platform technology to develop therapeutics that render calcified tissue and organs supple again.
It is the latest addition to the growing portfolio of Kizoo Technology Capital; a rejuvenation biotech investor focused on reversing age-related damage on a cellular and molecular level.
Elastrin’s lead asset is a nanoparticle conjugated with a novel monoclonal antibody to treat heart valve and vascular calcification.
“Elastin fibers are critical for the homeostasis of tissues around the body, including the skin, vasculature, and pulmonary tissues. As elastin fibers become damaged over time, arterial walls weaken, and the body’s physiological response results in aortic wall stiffening, aneurysms, and hypertension,” said Prof. Naren Vyavahare, Chief Scientific Officer at Elastrin Therapeutics.
The Elastrin team has developed a platform that can restore vascular health by removing pathological calcification, specifically from sites where elastin has been degraded. This is achieved via targeting albumin nanoparticles loaded with therapeutic agents directly to the tissue site of interest with the company’s proprietary anti-elastin monoclonal antibody. “This targeted delivery promises to improve the efficacy of therapeutic payloads as well as reduce side effects due to otherwise systemic administration. In addition, the nanoparticles result in slower release characteristics that improve the biodistribution of pharmaceuticals at the targeted exposure site,” said Douglas Mulhall, co-founder of Elastrin Therapeutics.
“Cardiovascular diseases are the number one cause of death globally, taking an estimated 18 million lives each year. On top of that, everyone above 30 years old is suffering from damage to the cardiovascular system, resulting in severe symptoms one day. Our technology can reverse damage to the arteries and heart and bring the body back to a state before the damage even occurred. This is a true game-changer in the industry and one of the puzzle pieces towards healthy aging. Nobody wants to live forever in an old and sick body, but we do want to live long in a healthy one,” said Matthias Breugelmans, CEO of Elastrin.
“We are proud to help Elastrin to open a new category in repairing significant damage of aging – tissue calcification and the damage to elastin fibers. This will allow for substantial rejuvenation of the cardiovascular system and restore organ function & skin elasticity to youthful levels,” says Frank Schueler, Managing Director of Kizoo Technology Capital.
“I am honored to be part of this highly ambitious endeavor to rejuvenate the circulatory system with a technology platform that has far-reaching potential,” said Patrick Burgermeister, Partner at Kizoo Technology Capital who will join the company’s Board of Directors.
About Elastrin Therapeutics Inc.
Elastrin Therapeutics is a South Carolina-based biotech developing novel therapies to reverse cardiovascular disease. Its underlying technology was developed by Dr. Naren Vyavahare during the last 20 years at Clemson University, in collaboration with Dr. Charles Rice, who developed the antibody. Our team built a proprietary platform that targets and restores degraded elastin by removing the harmful calcification that stiffens arteries. The platform significantly improves the efficacy of drugs and eliminates side effects by combining particle design with elastin targeting.
Further information can be found at www.elastrin-therapeutics.com
About KIZOO
KIZOO provides mentoring, seed, and early-stage financing with a focus on rejuvenation biotech. Having been entrepreneurs, VC, and mentors in both high-growth tech and biotech companies ourselves for many years with multiple exits and massive value created for the founders, Kizoo now brings this experience to the emerging field of rejuvenation biotech. We see it as a young industry that will eventually outgrow today’s largest technology markets.
As part of the Forever Healthy Group, Kizoo directly supports the creation of startups turning research on the root causes of aging into therapies and services for human application. Investments include Cellvie, Underdog, Revel Pharmaceuticals, Elevian, LIfT BioSiences, MAIA Biotechnology, Turn.bio, and others.
Forever Healthy’s other initiatives include evaluating new rejuvenation therapies, evidenced-based curation of the world’s cutting-edge medical knowledge, funding research projects on the root causes of aging, and hosting the annual Undoing Aging Conference.
Further information can be found at www.kizoo.com and www.forever-healthy.org

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Date Posted: March 3, 2021

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Bioage Clinical Trial for Unexplained Anemia of Aging

BioAge, in a recent press release, has announced the start of its phase 2a clinical trial in elderly patients with unexplained anemia of aging.

BioAge is a California-based company founded in 2015 with a very direct focus on aging. It utilizes a systems biology approach and AI-based drug discovery platform to target important pathways which are found to play a role in aging. The foundation of its platform is a large, longitudinal, human dataset containing the blood samples, medical records, and eventual longevity outcomes of patients. Currently, it is pursuing programs relating to immune decline and unexplained anemia of aging, the latter of which is the focus of the imminent clinical trial.

Unexplained anemia of aging

Anemia is a well-known condition in which patients often feel tired, dizzy, or weak due to a low level of red blood cells – the cells that carry vital oxygen to the body’s tissues. Most commonly associated with an iron deficiency, anemia can be brought on by multiple causes. It is not typically thought of as a disease of aging, but its prevalence does increase significantly in older populations. The cause of the anemia is usually straightforward in younger patients, such as low vitamin B or a genetic disorder such as thalassemia.

However, there is no identifiable cause for anemia in about a third of patients over the age of 65. This unexplained anemia in older adults comes at a surprising cost. Patients have reduced mobility and independence. Anemic patients also are much more likely to fall and have mortality rates that are triple to quadruple those of similarly aged non-anemic people. These factors, among others, result in a significant decline in quality of life and an increase in medical costs.

Hypoxia-Inducible Factor (HIF) and treatment with BGE-117

Through analysis of its aging database, BioAge has discovered that high HIF activity is associated with increased physical function, cognitive function, and extended lifespan. HIF affects a number of cellular processes, including the production of blood cells, glucose metabolism, and vascular remodeling. BGE-117 is a drug that inhibits an enzyme responsible for breaking down HIF. By inhibiting this enzyme, the circulating amount of HIF can increase dramatically. In fact, a previous clinical trial in 69 patients with chronic kidney disease showed BGE-117 to increase erythropoietin (EPO) in addition to being safe and well-tolerated.

The clinical trial

This Phase 2a trial for unexplained anemia of aging has begun enrolling patients over the age of 65. In the study, an oral dose of BGE-117 will be given to 80 patients (with an additional 80 receiving a placebo) daily for 12 weeks. The study is being conducted in Australia and is spread out over 15 clinical sites. The primary outcome will be hemoglobin levels and patient-reported scores on the FACIT-F scale, a quality-of-life questionnaire designed to evaluate the effect of fatigue on daily activities and function. Safety, pharmacokinetic, and pharmacodynamic data will be collected alongside exploratory aging biomarkers and muscle aging endpoints.

Dr. Kristen Fortney, CEO of BioAge, remarks:

UAA is both highly prevalent and highly morbid, dramatically decreasing quality of life in its patients and imposing a tremendous pharmacoeconomic burden. The lack of safe and effective treatments for this condition represents a major unmet clinical need… Because BGE-117 targets a critical pathway that is dysregulated as we age, it holds great promise for several acute and chronic conditions driven by muscle aging. Functional and biomarker data from this trial will guide our advancement of BGE-117 into additional indications, targeting multiple diseases of aging with large unmet needs, high prevalence, and huge markets.

Conclusion

While results are not expected until the first half of 2022, the longevity field is still at a stage at which clinical trials are launched infrequently, and each one is cause for excitement. Although the trial could very well fail, the outcomes of this study will be followed closely by patients with unexplained anemia of aging and the longevity community at large.

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Date Posted: March 2, 2021

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A Summary of NAD+ and Human Aging – Part 1

This is part one of a two-part article where we take a look at NAD+ biology, its history, how it relates to the biology of aging, and the potential for therapeutic interventions via the so-called NAD+ precursors.

What is NAD+?

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.

In metabolism, NAD facilitates redox reactions, carrying electrons from one reaction to another. This means that NAD is found in two forms in the cell; NAD+ is an oxidizing agent that takes electrons from other molecules in order to become its reduced form, NADH. NADH can then become a reducing agent that donates the electrons it carries. The transfer of electrons is one of the main functions of NAD, though it also performs other cellular processes, including acting as a substrate for enzymes that add or remove chemical groups from proteins in post-translational modifications.

NAD+ is created from simple building blocks, such as the amino acid tryptophan, and it is created in a more complex way via the intake of food that contains nicotinic acid (niacin) or other NAD+ precursors. These different pathways ultimately feed into a salvage pathway, which recycles them back into the active NAD+ form.

Nicotinamide adenine dinucleotide (NAD+) biology has seen a great deal of interest in the last few years, partially due to the discovery of two precursors of NAD+ biosynthesis, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which both increase NAD+ in multiple tissues.

Accumulating evidence suggests that NAD+ systemically d eclines with age in a variety of organisms, including rodents and humans, which contributes to the development of many age-related diseases. For this reason, there is a great deal of interest in creating potential interventions that increase NAD+ levels via precursors, thus delaying or even preventing certain aspects of age-related functional decline and diseases.

History of NAD+ research

Before we talk more about NAD+ precursors, let’s take a look at the history of NAD+ biology in order to get a better idea of the background and research that has taken place.

We have known about NAD+ for over a hundred years. Harden and Young originally discovered NAD+ back in 1906, when they discovered that it increased the rate of fermentation in yeast [1]. In the years following this, Euler-Chelpin, a German-born Swedish biochemist, identified that NAD+ was a nucleotide and, in 1929, received the Nobel Prize in Chemistry for his research on the fermentation of sugar and the enzymes involved in the resulting complex reactions.

In 1937, the American biochemist Conrad Elvehjem identified two vitamins, nicotinic acid and nicotinamide, which were deficient in people suffering from pellagra [2]. In 1949, Elvehjem showed that nicotinamide was able to prevent pellagra in dogs by increasing the production of NAD+ [3]. This discovery ended up with nicotinic acid and nicotinamide being classified as vitamin B3, and they are considered to be the original NAD+ precursors.

The first NAD+ gold rush

In 1963, there was a surge of interest in NAD+, when Chambon, Weill, and Mandel showed that NMN activated a previously unknown DNA-dependent polyadenylic acid-synthesizing nuclear enzyme [4]. This research subsequently led to the discovery of poly-ADP-ribose and poly-ADP-ribose polymerases (PARPs), which are part of a family of proteins involved in a number of cellular processes, including DNA repair, maintaining genomic stability, and programmed cell death [5].

In 1965, Hayaishi and his team started to reveal the NAD+ pathway, how it was created via tryptophan, and the NAD+ intermediate nicotinic acid mononucleotide (NMN) [6]. In 1966, Gholson suggested that there was an active turnover cycle of NAD+, which, at the time, performed “an important but as yet unknown function” relating to cellular metabolism [7]. A decade later, in 1976, this was confirmed by Rechsteiner and his team when they published evidence for the rapid turnover of NAD+; this further supported the suggestion that NAD+ had another major function in eukaryotic cells in addition to its established role in oxidation and reduction [8].

In 1989, Lee and his research team incubated NAD+ with extracts from sea urchin eggs, discovering a new NAD+ metabolite, cyclic ADP-ribose [9]. The enzyme ADP-ribosyl cyclase was initially identified in 1991 by Lee and his team in Aplysia, a type of large sea slug [10]. It was later found to exist in mammals as CD38, which was confirmed by Lee, Walseth, and Lee in 1992 [11].

The second NAD+ gold rush

There was another surge of interest in NAD+ biology that happened in the year 2000 and has lasted until the present. The study that started the renewed interest was published by Guarente in 2000, which showed that yeast SIR2 (silent information regulator 2) and the related mouse ortholog, SIRT1, both had NAD+ dependent protein deacetylase activity [12]. Adding further fuel to the fire, in 2001, human nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT) was successfully isolated [13]. NMNAT is an important NAD+ biosynthetic enzyme, so its isolation and characterization was an important step.

Next, nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme responsible for converting nicotinamide into NAD+, was isolated and characterized between 2002-2004 [14-15].

In 2004, nicotinamide riboside was shown to lead to the creation of NAD+ via nicotinamide riboside kinases (NRKs). This study demonstrated that nicotinic acid mononucleotide was not the only path to NAD+ biosynthesis [16].

Is this a third NAD+ gold rush?

While it’s fair to say that interest in NAD+ biology, especially in the context of aging, has not really gone away since the second gold rush period, if anything, the level of interest has skyrocketed in the last few years.

There are now many companies involved in offering supplements based on NAD+ precursors, such as ChromaDex and Elysium Health in the case of nicotinamide riboside along with NOVOS, which offers nicotinamide mononucleotide.

These all aim to increase NAD+ levels, as recent studies appear to suggest that NAD+ systemically declines with age in a variety of organisms, including rodents and humans, which contributes to the development of many age-related diseases. For this reason, there is a great deal of interest in creating potential interventions that increase NAD+ levels via precursors, thus delaying or even preventing certain aspects of age-related functional decline and diseases.

A 2012 study reported that there is a significant age-related decline of NAD+ levels in skin, and while not exact, the average level of concentration seems to fall by a minimum of 50% [17]. The difference between newborns and adults, for example, appears to be several-fold lower, according to the findings of the study.

Regarding the brain, a 2015 study saw researchers measuring intracellular NAD+ and NADH concentrations and the NAD+/NADH ratio in the human brain, detecting the age-dependent changes in NAD contents and the redox state associated with aging [18].

Another study from 2019 also concluded that an age-dependent decline of the NAD+ levels in the brain was also observed [19]. Taken together, these two studies suggest that there is a decline of NAD+ in the brain of between ~10% to ~25% between the period of young adulthood and old age.

Nuchido is another company seeking to address loss of NAD+, but it is taking a slightly different approach to the problem. Rather than trying to increase the amount of precursors available to be converted into NAD+, this company is instead targeting the age-related inflammation that prevents the body from making its own. Nuchido CEO, Dr. Nichola Conlon, recently wrote an article, The Intertwined Nature of NAD+, CD38, and Senescence, which explores the complexity of NAD+ and how it interacts with inflammatory signals.

If you want to find out more about age-related NAD+ decline, we take an in-depth look at the various ways in which this happens in Why NAD+ Declines During Aging.

2020 was a good year for NAD+ research, with a study showing that Niacin increases NAD+ significantly in human trials, at least in aged human muscle tissue [20]. Niacin has been a popular and cheap supplement for many years, and studies like this suggest that this old dog may have a few new tricks.

The quest to restore NAD+ has picked up even more pace in 2021, with a study showing that increasing NAD+ reduces amyloids and benefits mitochondria and that human cells, aged mice, and nematodes all showed similar results [21]. This gives hope for the treatment of age-related amyloidosis and mitochondrial dysfunction, and, as both are a feature of age-related muscle decline, NAD+ restoration may be a potential solution to age related frailty.

That brings us to the end of our potted history of NAD+; almost half a century after the first surge of interest, we are now enjoying a new era of research and discovery in NAD+ biology. Join us for part two of this article, where we delve deeper into the NAD world.

Literature

[1] Harden, A., & Young, W. J. (1906, October). The alcoholic ferment of yeast-juice. Part II.—The coferment of yeast-juice. In Proc. R. Soc. Lond. B (Vol. 78, No. 526, pp. 369-375). The Royal Society.

[2] Simoni, R. D., Hill, R. L., & Vaughan, M. (2002). Copper as an Essential Nutrient and Nicotinic Acid as the Anti-black Tongue (Pelagra) Factor: the Work of Conrad Arnold Elvehjem. Journal of Biological Chemistry, 277(34), e22-e22.

[3] Elvehjem, C. A. (1949). Pellagra: A Deficiency Disease. Proceedings of the American Philosophical Society, 93(4), 335-339.

[4] Chambon, P., Weill, J. D., & Mandel, P. (1963). Nicotinamide mononucleotide activation of a new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochemical and biophysical research communications, 11(1), 39-43.

[5] Herceg, Z., & Wang, Z. Q. (2001). Functions of poly (ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 477(1), 97-110.

[6] Ikeda, M., Tsuji, H., Nakamura, S., Ichiyama, A., Nishizuka, Y., & Hayaishi, O. (1965). Studies on the biosynthesis of nicotinamide adenine dinucleotide II. a role of picolinic carboxylase in the biosynthesis of nicotinamide adenine dinucleotide from tryptophan in mammals. Journal of Biological Chemistry, 240(3), 1395-1401.

[7] Gholson, R. K. (1966). The pyridine nucleotide cycle. Nature, 212(5065), 933.

[8] Rechsteiner, M., Hillyard, D., & Olivera, B. M. (1976). Magnitude and significance of NAD turnover in human cell line D98/AH2. Nature, 259(5545), 695.

[9] Lee, H. C., Walseth, T. F., Bratt, G. T., Hayes, R. N., & Clapper, D. (1989). Structural determination of a cyclic metabolite of NAD+ with intracellular Ca2+-mobilizing activity. Journal of Biological Chemistry, 264(3), 1608-1615.

[10] Lee, H. J., Hong, Y. S., Jun, W., & Yang, S. J. (2015). Nicotinamide riboside ameliorates hepatic metaflammation by modulating NLRP3 inflammasome in a rodent model of type 2 diabetes. Journal of medicinal food, 18(11), 1207-1213.

[11] Walseth, T. F., & Lee, H. C. (1992). Similarities in amino acid sequences of Aplysia ADP-ribosyl cyclase and human lymphocyte antigen CD38. Trends in biochemical sciences, 17(12), 495.

[12] Imai, S. I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000). Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature, 403(6771), 795.

[13] Schweiger, M., Hennig, K., Lerner, F., Niere, M., Hirsch-Kauffmann, M., Specht, T., … & Ziegler, M. (2001). Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis. FEBS letters, 492(1-2), 95-100.

[14] Revollo, J. R., Grimm, A. A., & Imai, S. I. (2004). The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. Journal of Biological Chemistry, 279(49), 50754-50763.

[15] Rongvaux, A., Shea, R. J., Mulks, M. H., Gigot, D., Urbain, J., Leo, O., & Andris, F. (2002). Pre‐B‐cell colony‐enhancing factor, whose expression is up‐regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis. European journal of immunology, 32(11), 3225-3234.

[16] Bieganowski, P., & Brenner, C. (2004). Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell, 117(4), 495-502.

[17] Massudi, H., Grant, R., Braidy, N., Guest, J., Farnsworth, B., & Guillemin, G. J. (2012). Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PloS one, 7(7), e42357.

[18] Zhu, X. H., Lu, M., Lee, B. Y., Ugurbil, K., & Chen, W. (2015). In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proceedings of the National Academy of Sciences, 112(9), 2876-2881.

[19] Bagga, P., Hariharan, H., Wilson, N. E., Beer, J. C., Shinohara, R. T., Elliott, M. A., … & Detre, J. A. (2020). Single-Voxel 1H MR spectroscopy of cerebral nicotinamide adenine dinucleotide (NAD+) in humans at 7T using a 32-channel volume coil. Magnetic Resonance in Medicine, 83(3), 806-814.

[20] Pirinen, E., Auranen, M., Khan, N. A., Brilhante, V., Urho, N., Pessia, A., … & Haimilahti, K. (2020). Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell Metabolism.

[21] Romani, M., Sorrentino, V., Oh, C. M., Li, H., de Lima, T. I., Zhang, H., … & Auwerx, J. (2021). NAD+ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle. Cell reports, 34(3), 108660.

Date Posted: March 2, 2021

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The Dog Aging Project Is Ready for Takeoff

Almost three years ago, Dr. Matt Kaeberlein, a Professor of Pathology and an Adjunct Professor of both Genome Sciences and Oral Health Sciences at the University of Washington in Seattle, outlined the nascent Dog Aging Project (DAP) for our readers in an extensive interview. Along with the intrinsic value of helping our beloved pets live longer, DAP also seeks to establish dogs as a highly effective platform for studying aging in humans.

Now, with the foundational phase of the project nearing completion, we have asked Dr. Kaeberlein to give us an update, and he has responded with some exciting news. Our talk with one of the world’s leading authorities on aging also touches on several other hot topics, including rapamycin and geroscience in the age of COVID-19.

We interviewed you about DAP back in 2018. Maybe you can walk us through the progress you have made. Where does it stand now?

Around the same time, we got a large grant from the NIH, about 5 million dollars a year, to build and carry out a longitudinal study of aging in dogs and to fund our rapamycin clinical trial. We refer to the rapamycin trial as TRIAD: Test of Rapamycin In Aging Dogs. There are two big parts to the Dog Aging Project. One is a true observational longitudinal study of aging, and the other is TRIAD, and most of the time so far has been spent building the infrastructure to carry this out.

The goal of the longitudinal study initially was to enroll 10,000 dogs, but we have expanded this with a new goal of 100,000 dogs enrolled in what we call the Dog Aging Project Pack. For each dog in the pack, we obtain high-resolution data on the dog’s environment and health history through owner surveys and electronic veterinary medical records. At this point, we are nearing 30,000 dogs enrolled in the Pack.

From the Pack, we are selecting 10,000 dogs to have their genomes sequenced along with owner survey data and veterinary medical records. That is what we call the Foundation group. A thousand dogs are selected for what we call the Precision group, and that’s a systems biology study where, every year, in addition to these dogs’ genome sequencing, we will collect their fecal microbiome, blood metabolome data, blood epigenome data, and comprehensive chemistry from blood, and there are also annual veterinary visits. TRIAD is designed to have 500 dogs come in for the initial visit with the goal that 350 of those dogs will be randomized into the clinical trial, which is half rapamycin, half placebo.

You can imagine that, first, there is a ton of infrastructure on the computing side and the survey instruments that had to be built. Basically, that is 95% built. We have a partnership with the Broad Institute, and all the data that comes into the Dog Aging Project is then eventually sent to its cloud computing Terra platform, where it can be accessed. One of the main features of the Dog Aging Project is that we are an open science project.

We want to stimulate discovery outside of our team, and our plan is to release the data that we have collected in annual installments to the scientific community and eventually to the public. Because of COVID, we pushed back all the stuff that requires dogs to come into the veterinary clinic since, like medical human hospitals, veterinarians only wanted to see patients who needed to be there during COVID.

So, like I said, 95% of the project infrastructure is built, but we are not yet having dogs in the clinic. We have focused mostly on collecting data through survey instruments. We have rolled out a large survey that really captures as much information as we can about the dogs, some information about the owners’ demographics, and a lot of information about the environment that each dog lives in along with the dog’s behavior and comprehensive health history. This Health and Life Experiences survey, which we call HLES, has been completed for almost 30,000 dogs. This is now one of the largest citizen science projects in the world.

We are getting our first longitudinal snapshot right now, as the very first dogs to enter the Pack are reaching their one-year anniversary and their owners are being asked to update the HLES with any changes to their dogs’ environment or health status. This will continue for every dog in the Pack once each year for the rest of their lives. This is going to be a super-rich data set, and we’ll be able to see how those dogs are aging, what environmental, dietary, and genetic factors might correlate with health outcomes during aging, and a baseline of what aging looks like in dogs.

Nobody has ever done that. One of the things that people don’t really appreciate is that unlike in human medicine, in veterinary medicine, there is no geriatric subspecialty. There are no veterinarian clinicians who are trained specifically to understand what happens during aging in our pets, and so this is an opportunity to actually provide this information to the veterinary community.

The other thing that we have added that wasn’t part of the initial plan, but that I’m super excited about, is a second survey that is specifically dedicated to cognitive function and dementia in dogs. There is a validated survey instrument for diagnosing canine cognitive dysfunction, which is a disease that looks somewhat like Alzheimer’s in dogs. It has some of the same neuropathological hallmarks. We’re hoping that this survey will actually be able to detect changes in cognitive function associated with aging that don’t reach the threshold of dementia. If we’re able to do that, it gives us a really important insight.

I have a grant proposal that, if funded, will allow us to expand our studies of cognitive aging into molecular sorts of questions like amyloid beta. I think that companion dogs potentially offer a super-powerful model of dementia in people. There is a whole collection of cognitive disorders that share some similarities but clinically present very differently. I think that dogs potentially offer an opportunity to understand some of the factors that influence cognitive aging because they do show cognitive changes with age that look very similar to aging in people.

You told us back in 2018 about the rapamycin trial coming up. What is the situation on that front?

I already mentioned that the intention is to select up to 500 dogs from the pack. In order to be eligible for the rapamycin trial, the dogs have to be at least 7 years old and weigh between 40 and 100 pounds. That’s because big dogs age faster than small dogs, and we need to have a middle-aged cohort in order to have the statistical power to detect the changes in lifespan that are our primary endpoint.

Unlike the Foundation or Precision cohorts, where owners can go to their own veterinarians, all the clinical components of TRIAD will be carried out at seven different veterinary teaching hospitals around the United States. Obviously, that means the owners have to be willing to take their dogs to these clinical sites twice a year for the duration of the study, which limits the geography. Then, there’s a training and consent process that the owners go through before we will schedule them for their first appointments at the hospitals. We want to make sure that the owners in TRIAD understand what is involved before we bring them in for their first visit.

We haven’t had any dogs come into the clinic yet because of the pandemic. Our expectation is that we’ll have the first few dogs probably in May, and then we’ll gradually ramp up. Our target is to have a hundred dogs enrolled in the trial by the end of 2021 and the remaining 250 randomized in the first half of 2022. This is what we are powered for: to see a 15% effect on lifespan over three years.

Secondary endpoints include cardiac function, which is one of the reasons we’re working with the hospitals; they all have outstanding cardiology teams. Cognitive function is another secondary endpoint, and we’re very interested in disease incidence, particularly cancer. We predict that rapamycin could reduce cancer incidence in dogs. Activity is a secondary endpoint too.

We’ve decided to go with a one-year treatment followed by two years of follow-up. This is based in part on the human clinical data with rapamycin derivatives. We want to minimize the risk to all the participants. Owners’ fatigue is also a factor: after talking with a lot of people, it became clear to us that asking owners to give a study drug for a randomized, double-blind, placebo-controlled trial to their dogs for three years was asking a lot.

The drug will be given once a week based on the human data from clinical trials with everolimus, which is a rapamycin derivative. It seems that an equivalent total dose given once a week rather than daily has better efficacy with reduced side effects. We are using a form of rapamycin that is coated for enteric release. It’s not the eRapa (encapsulated rapamycin) that’s used in mice, that’s a different formulation, but it is also not exactly the same as generic rapamycin (sirolimus) tablets that organ transplant patients take.

Will you be accounting for differences between male and female dogs?

We don’t know if there are differences in rapamycin efficacy between male and female dogs yet. If you’re familiar with the mouse data, at least at lower doses of rapamycin, female mice tend to show bigger lifespan effects than male mice. That’s not necessarily true for all of the functional measures or what people call healthspan measures. That effect is likely due to the fact that female mice tend to have higher steady-state blood levels than males do.

However, I don’t think there’s any evidence to suggest that there are large sex-dependent effects of rapamycin in people, and there’s no data yet in dogs. So, the answer to your question is, we are aware that that could be the situation, but we don’t have any particular reason to think that’s going to happen. We are stratifying by sex. Our goal is to equally enroll male and female dogs and roughly equally distribute them between placebo and treatment groups. That’s the best we can do at this point.

What about breed differences? Do you expect any problems there?

We are not restricting by breed. We were anticipating that we will have roughly half purebred versus mixed breed. We decided not to stratify based on that. We’re going to limit the number of any one breed in the study so that most popular breeds don’t get overrepresented, like golden retrievers.

I’ve said repeatedly that there’s intrinsic value to improving health during aging in our pets, but if we see big effects from rapamycin in dogs, that certainly enhances enthusiasm for continuing to look for similar effects in people. In that regard, the fact that dogs are genetically heterogeneous is important. The question is not whether rapamycin will work in German Shepherds, the question is whether it will work in a heterogeneous population that looks genetically something like the human population. So, we want to capture that genetic diversity, and we will have full genome sequencing on every dog in TRIAD. Unless there are huge genetic signals, I don’t think we have enough dogs to map genetic variants to efficacy in the trial, but there are large genetic interactions, we might be able to identify some of them.

Where do we stand with rapamycin in general? Has it been living up to the expectations?

I think if you look at the preclinical data in mice, rapamycin is head and shoulders above anything else in terms of interventions that have been tested repeatedly, work repeatedly, and appear to broadly delay aging in mice. Compare it to metformin, which doesn’t extend lifespan in mice most of the time, and the health benefits of metformin in mice are pretty much restricted to cancer in certain backgrounds and metabolic outcomes. Metformin is a different beast because there’s a lot of human data that actually supports the idea that metformin might affect aging in people, but I think if you were to pick a drug based only on the mouse data and you were being honest with yourself, rapamycin is the only game in town. There is nothing else in mice that comes anywhere near the data that we’ve got for rapamycin.

Then the question is, does the human data for rapamycin support the idea that it actually has impact on age-related outcomes in humans? I think the fair answer is that nobody has done a great clinical trial with rapamycin. There were two trials with everolimus, which is a derivative of rapamycin. If we accept for the purpose of this conversation that those two drugs are biochemically pretty much identical, the data is pretty good. In the two Phase 2 clinical trials, there was a positive effect on immune function in healthy older people from six weeks of treatment with a rapamycin derivative.

They responded better to a flu vaccine and they got less infections. So, that’s at least as good as you could hope for. There have been a couple of small clinical trials for safety showing that at lower doses of rapamycin, there are little to no side effects. There was one very small study looking at skin senescence in people, but we really just don’t have any data to say one way or the other. I think there’s a lot of confusion and misinformation out there when the data comes from people who have had organ transplants, who are taking high doses of the drug along with a bunch of immunosuppressants. You can’t really look at those patients as a reflection of what rapamycin might do at lower doses in healthy individuals.

In the previous interview you gave us, you pointed at insufficient funding as the main problem that hampers progress in the longevity field. Do you think this is still the case, or maybe we’ve already seen some commercialization of the field?

There’s a couple of things to say. One is that I think it’s very exciting that there is a lot of interest and some resources coming into the field on the commercial side, and clearly that momentum is building. I also think it’s important to recognize that if you take Calico out as a hybrid of a company and academia, the total amount of money that’s coming into this field on the for-profit side is a tiny drop in the bucket compared to the annual budget of the NIH or even the NIA. So, I still would argue that the resources that are coming to the field are miniscule compared to what they should be, given where the science is at and the potential benefit for human health.

This needs to change at the federal funding level. I don’t think you’re ever going to see the same kind of impact from private investment. I would love to be proven wrong, and you never know what might happen, but I think that even though more is coming into the field that way, it’s not as impactful as if aging biology went from 0.5% of NIH funding to 5% of NIH funding. That would be a tenfold increase overnight, which is still a small proportion of NIH funding given the impact of this biology on human health. People have this perception that all this money is coming through the commercial side, and while it’s true compared to the past, it’s still not that much in the grand scheme of things.

I’m thinking of what you said about the openness of your project and the wide availability of the results, which is something that commercial enterprises are not really good at. You are saying that there is still not a lot of money on the for-profit side, but could it already be harming cooperation?

It’s possible. It’s hard to know. Because people aren’t sharing, we don’t really know what they’ve got. Calico, again, is an interesting example because they’re kind of in the middle, they published some papers, but they obviously must have a lot of data that they’re not publishing, and so we don’t really know how important or impactful that data would be. Again, though, I would say because 95 to maybe 99 percent of actual research in this field is happening in academia right now, I don’t think it’s a huge barrier to progress.

That’s my personal opinion, and maybe I shouldn’t say this, but I’m going to anyway. I think that most of what’s happening right now in the anti-aging for-profit arena is really not cutting-edge science. There are a lot of people coming up with their own ideas who don’t have sufficient background knowledge or understanding of aging, and so they’re making a lot of maybe newbie mistakes that could be avoided if they didn’t come in thinking they already knew everything. But they do come in thinking they know everything and that they’re going to solve aging, and they just throw a bunch of money at it, and it fails miserably. That’s my impression from a lot of what is happening on the for-profit side.

I think that’s changing. I also think some of the newer companies that have come in recently are a bit more sophisticated; they actually have some people with appropriate background and knowledge to guide them. However, I’m quite skeptical that there is a ton of super-valuable data in the for-profit sector right now.

On the NIH side, the tide is starting to turn as well. Do you feel it?

I do, and I think the tide is turning in a way that I’m personally very pleased about. An RFA (request for applications) came out fairly recently for clinical trials to target the hallmarks of aging, which is great. That clearly shows interest at the NIH in this area, but that RFA was released by the NIA, the National Institute of Aging. If it had come from the Director’s Office, I would be super excited because then it would show me that this has gotten beyond the NIA and permeated the NIH more broadly.

Interestingly, in a way, it is already happening. For example, if you look at cancer, the NCI (National Cancer Institute), if you look at diabetes, the NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases), they’re now studying aging processes. They’re not calling it biology of aging, but they’re interested in senescence, or in changes in mitochondrial function that go along with age, or age-related inflammation that we’re studying as a hallmark of aging.

They’re studying it in the context of their disease, but they’re starting to view these things from the perspective of aging. Honestly, I don’t care if they call it aging, I don’t care if the money flows through the NIA or it continues to go through each individual Institute. I’m pleased by the fact that scientists who haven’t previously focused on aging biology are starting to incorporate it into their research, even if they don’t realize it.

In a paper you co-authored, “Geroscience in the Age of COVID-19”, you argue that “one of the most important lessons to be learned from this pandemic is the need to therapeutically address degenerative aging processes to prevent aging-related ill health as a whole”. Many scientists have called for the same approach, and we ran an editorial about that. Do you think we have been heard?

I don’t know. My intuition is that these changes were already happening. Certainly, the pandemic might accelerate them, and I think that papers and editorials on this topic have helped to make the point that COVID-19 is an age-related disease. Hopefully, this will shift mindsets a little bit towards recognition of how important aging is, specifically in the context of COVID-19 but not exclusively.

For example, before COVID-19, we accepted that 250 to 500 thousand people a year worldwide would die from influenza, mostly old people. There’s an important biology for this disease that we have accepted for a long, long time will kill half a million people a year, and we could potentially do something about it. So, we need to continue to get that message out there, and hopefully it will help accelerate this recognition that there is a biology of aging that is malleable, that we know enough to actually have an impact and hopefully protect the most vulnerable people from COVID-19, influenza, and other infectious diseases.

I assume that you are doing research apart from the Dog Aging Project. Would you like to tell us what you are working on?

Sure. My lab has always been focused on conserved mechanisms of aging. We still work in yeast and C. elegans and mice. Our mouse studies are primarily focused on metabolic diseases, mitochondrial diseases. We have a project on a metabolic disease called maple syrup urine disease. We have an obesity project, and then we have normal aging, so we kind of work on a lot, but it’s all from the perspective of understanding how the hallmarks of aging, the molecular mechanisms of aging, impact these various diseases in different mouse models. A lot of what we’re interested in, as you might guess, is mTOR biology, rapamycin, and other mTOR inhibitors.

We published a paper last year on the ability of rapamycin to reverse periodontal disease in mice. We haven’t yet moved this into the clinic, but I’m hopeful because periodontal disease is unique from a clinical trials perspective: it is a very easy endpoint to measure in humans, and it’s very non-invasive. You go to the dentist, and they do a pocket depth measurement and an x-ray. They look at your gingival inflammation, and you can sequence the oral microbiome, and those are the three clinically defining features of periodontal disease. So, it’s actually quite an easy clinical trial to carry out. I’m hopeful that we’ll be able to get a clinical trial going to see whether rapamycin, or a couple of other interventions that we’ve got, can have a clinical impact on periodontal disease in people.

Unfortunately, it is a ridiculous example of how the for-profit system and the regulatory system is broken. There is a very good chance that we will be able to reverse periodontal disease in people. I believe that’s true, and our preclinical data is rock solid for rapamycin and looking pretty good for another intervention, and yet there is very little interest in commercializing that, not because people don’t think it’s going to work, not because rapamycin is off-patent, but because of the way that dental insurance is billed and they don’t think they’ll be able to get reimbursed. It’s not worth the risk of an FDA clinical trial for them.

We have a really nice endpoint where there’s an opportunity to have proof of principle that a geroscience intervention works for an age-related disease in a pretty short period of time. Like I said, there’s rock-solid preclinical data, better than the preclinical data supporting 90% of the biotechs that are out there, but people aren’t interested in commercializing it because of the way that dental insurance is billed. I was sort of surprised that that’s the reality. I haven’t given up on the idea, but it’s a really unfortunate consequence of the way in which we regulate and charge for healthcare in this country.

I feel that we have become accustomed to this US-centric approach, but other countries do health insurance differently. Do you think that those differences in regulation, and maybe in the way societies work in general, can lead to a breakthrough in longevity research coming from, say, China, because they have a huge problem with their one child policy and because they are less scrupulous with regulation, privacy, and human rights?

I think it’s certainly possible, but, obviously, most of the money right now is focused on drug approval in the United States. That’s just the way the system works. So, it’s absolutely possible that a breakthrough may come from a different country, but, unless things change, they’re still going to want to get FDA approval and have to go through that process. I absolutely agree with the premise that there is exciting aging research going on outside of the United States, and it would not surprise me at all if something important on the therapeutic side gets tested and validated first somewhere else before coming into the US FDA approval system. China, sure, but that’s not the only place for this. It’s wherever the science is happening and wherever the infrastructure is in place for for-profit entities to come in.

We thank Dr. Kaeberlein for taking the time to talk to us, and we look forward to seeing the future results and developments of the Dog Aging Project.

Date Posted: March 1, 2021

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Rejuvenation Roundup February 2021

As rejuvenation research continues to grow and develop, so do we here at lifespan.io. This month’s Roundup features quite a few interesting studies along with things that we’re doing to make these studies more accessible to the public.

LEAF News

Developing Our Ethics Code of Longevity Journalism: Fact-based journalism is critical to reporting on advances in rejuvenation biotechnology and related topics.

lifespan.io Announces Promotions and Expansion: Thanks to the support of our dedicated readers and the Lifespan Heroes, our organization continues to grow.

Lifespan News

Solving Gray Hair: This episode’s other topics include the fact that rapamycin isn’t a caloric restriction mimetic while glucosamine may be one, and senolytics have effects on age-related cognitive decline while artificial intelligence is being explored in longevity medicine.

Depression and Brain Aging: Additional topics include stem cell neurons for Parkinson’s disease, the utility of contacting Congress, a database for aging in mice, and Salk scientists receiving $1.2 million to study aging of the brain.

Parasitic Worm Infestation for Longevity: Helminths might be used to fight inflammaging; additionally, Brent discusses the effects of NAD+ on mitochondria and amyloids, senescent cells in the aging retina, Longevity Therapeutics 2021, and our Science to Save the World episode on cooling the planet.

Longevity Therapeutics 2021

We learned a great deal from the multiple presenters at this scientific conference, and there was so much information that we had to break out our experiences into a four-part series: Part 1 Part 2 Part 3 Part 4

Rejuvenation Roundup Podcast

Ryan O’Shea of Future Grind hosts this month’s podcast, showcasing the events and research discussed here.

Advocacy Digest

Longevity Pharmacology Comes of Age: Dr. João Pedro de Magalhães explains how pharmaceutical development of longevity-increasing compounds is a growing field.

Replacing Aging With Jean Hébert: Dr. Jean Hébert takes the stance that replacement of tissues and organs, as opposed to pharmacological interventions, will be the future of effective rejuvenation.

Research Roundup

Neurons from Stem Cells Alleviate Parkinson’s Disease in Rats: Researchers have reported on their success in priming stem cells to differentiate into dopaminergic neurons in rat brains.

Parasitic Worm Infestation for Longevity: Helminths, parasitic organisms that live in the intestines, produce natural immunosuppressants that may be actually beneficial for human health.

The Intertwined Nature of NAD+, CD38, and Senescence: Aging is complicated, and multiple hallmarks of aging are shown to affect one another.

Increasing NAD+ Reduces Amyloids and Benefits Mitochondria: Further showing how aging hallmarks affect one another, this study provides evidence that the hallmarks of proteostasis and mitochondrial dysfunction are shown to be positively affected by additional NAD+.

Senescent Cells in the Aging Retina: Senescent cells and their secretions are shown to contribute to age-related macular degeneration.

Male and Female Gut Microbiomes Converge With Age: While the natural microbiomes of men and woman are different, aging causes them to become the same.

Proposing Gerobiotics as a New Gut Microbiome Research Field: This review explains that age-related changes of gut flora represent a distinct field within geroscience, and the authors coin the term ‘gerobiotics’ to describe it.

Measuring Age With a Bloodborne Neural Protein: A study shows that the presence of neurofilament light chain in the bloodstream signifies damage to the nervous system.

Atrophy of the Neuronal Circadian Clock Is a Disease of Aging: Victor Bjoerk presents his paper showing that there is a small population of neurons that governs the circadian clock, and as they age, the circadian rhythm is disrupted.

SIRT3 Replenishment Reverses Lung Fibrosis in Mice: Fibrosis is a balance, but aging puts its thumb on the scale. Mouse research shows that the sirtuin SIRT3 may restore this balance.

Geroprotective effects of Alzheimer’s disease drug candidates: This research shows that the geroprotective AD drug candidates J147 and CMS121 prevent age-associated disease in both brain and kidney

GDF11 alleviates secondary brain injury after intracerebral hemorrhage: This drug suppresses the feedback loop involved in reactive oxygen species and mitochondria, resulting in amelioration of neural damage

The goal of geroscience is life extension: This review examines multiple drugs that have been reported to increase healthspan, but only a few of them increase lifespan.

A Wnt5a-Cdc42 axis controls aging and rejuvenation of hair-follicle stem cells: This paper explains how molecular signaling leads to hair loss in aging and that this signaling can be restored to its youthful state.

Senescent cells and the incidence of age‐related diseases: This research shows that cellular senescence and multiple age-related diseases are closely linked.

Quantum Dot Nanomedicine Dramatically Improves Metformin and Nicotinamide Mononucleotide Effectiveness in Mice: Quantum dot formulations are uptaken through the small intestine and liver differently than normal drugs, and this research shows that they increase the potency of NMN and metformin.

Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition: This research shows that pathological blood vessels are closely related to cellular senescence.

An integrative study of five biological clocks in somatic and mental health: Many biomarker-based clocks give different and largely unrelated results, suggesting that a multi-clock approach to measuring biological age is better than using one.

Effects of Platelet-Rich Plasma on Cellular Populations of the Central Nervous System: The Influence of Donor Age: As other research has shown, old blood contains deleterious factors not found in young blood, and this research shows its comparative effects.

Cost-free lifespan extension via optimization of gene expression in adulthood aligns with the developmental theory of ageing: This research shows that, at least in C. elegans, genes that are beneficial during developmental stages are harmful in adulthood.

The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19: This paper suggests that clinical trials should be undertaken to determine whether mTORC1 inhibitors are useful against COVID-19 infection.

Healthy life expectancy by frailty state in Europe from 2004 to 2015: findings from SHARE: This study examines the relationship between frailty and life expectancy along with how that relationship has changed over eleven years.

News Nuggets

The NIA Is Funding Clinical Trials Against Aging: The National Institutes of Aging in the United States is sponsoring trials of interventions that directly affect aging.

ChromaDex Announces $25 Million Private Placement of Common Stock: 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.

Humacyte in Deal to Develop Prosthetic Vasculature: Humacyte, which is developing bioengineered vascular tissue, is entering into a merger with a special purpose acquisitions company in order to raise funds with which to grow.

Digital Health Company Bold Lands $7 Million: Thanks to an injection of seed round cash, a new company, Bold, joins the growing pool of organizations that are focused on wellness and disease prevention.

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Date Posted: February 26, 2021

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Digital Health Company Bold Lands $7 Million

Thanks to an injection of seed round cash, a new company, Bold, joins the growing pool of organizations that are focused on wellness and disease prevention.

The rising interest in wellness and healthy aging

It’s no secret that the interest in digital health and wellness has risen in recent years along with the popularity of concepts such as healthy aging. This $7 million seed round, which included funds from Andreessen Horowitz, Khosla Ventures, Primetime Partners, and GingerBread Capital, will help to get the company set up and primed for growth in what is a rapidly expanding market for digital wellness and healthy aging services.

The company claims to be using a research-based digital health platform to help its customers get fitter and healthier. As part of this, the company is offering customers a personalized exercise program that is tailored to their individual needs. The idea here is to help customers get fitter and healthier so that they are more likely to remain independent for longer as they get older. Staying active may also help to delay the onset of some age-related diseases.

Bold claims that its initial program has reduced the risk of falls, which often cause fatal complications in older people, for its clients due to improvements in strength, balance, and mobility as a result of its tailored exercise regimens.

The company launched at a fortuitous time, as this was just before the COVID-19 pandemic hit and gyms, senior centers, and other fitness venues were closed. This created a vacuum, and it was one that Bold was well placed to fill. As people were limited in exercise options and places in which to do it due to lockdowns, they started to seek ways to keep fit at home but in a way that kept them engaged and feeling part of something. For many of them, Bold addressed that need.

The company is expected to announce partnerships with health insurance plans that will make its fitness programs available to many more older people.

Healthy aging is an oxymoron

The demand for such wellness and healthy aging services is rising quickly. Of course, as the aging processes are the foundation of age-related disease, there is no such thing as healthy aging; it is an oxymoron. Indeed, our field is busy developing technologies that will hopefully far surpass what is currently possible with just exercise, offering true rejuvenation of aged tissues and organs.

However, for now, exercise is one of the best ways we have to slow down aging, and Bold joins the growing pool of companies focusing on wellness, disease prevention, and the idea of healthy aging. While the latter is a meaningless mantra to us, the former has some merit, and there are plenty of studies showing that exercise and keeping fit can help slow down the age-related loss of muscle mass, balance, and stability, thus delaying the loss of independence that such deterioration ultimately brings.

Conclusion

This trend of healthy aging and wellness is likely to continue for some time, and it is no doubt a positive thing to encourage people to be more healthy and active, especially as they get older; however, if our field is successful, such things will pale in comparison to what true rejuvenation could achieve.

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Date Posted: February 25, 2021

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Measuring Age With a Bloodborne Neural Protein

A new study shows that functional deterioration of the nervous system contributes to late-life mortality and identifies a related bloodborne biomarker for all-cause mortality [1].

Neurofilament light chain (NfL) is a structural protein found in nerve cells. The nervous system has been implicated in aging and longevity, so the fact that NfL can be detected in human bodily fluids makes it potentially useful as a biomarker for aging. NfL levels are known to increase with age and in response to neurodegenerative diseases, strengthening the case for its use as a biomarker.

To test the idea, an international team of scientists measured NfL levels in blood plasma from a cohort of people aged 21 to 107. They found a non-linear increase and greater variability with age. Plasma proteome data had already been generated from the same cohort, and NfL levels correlated with 53 of the proteins (out of roughly 1300). The proteins correlated with NfL levels are involved in apoptosis as well as synapse formation and plasticity, supporting the notion that plasma NfL levels reflect the activity of pathways associated with neuronal function.

The researchers then evaluated NfL as a predictor of mortality. They collected blood from separate cohorts of centenarians and nonagenarians, measured NfL levels, and tracked the cohorts over the next few years (or until death). They used activity of daily living (ADL) and Mini-Mental State Examination (MMSE) measures to assess the health of the participants. Overall, individuals with lower NfL levels lived longer than those with higher levels and did better on MMSE and ADL measures, though the difference was smaller for ADL.

Finally, the team also showed that NfL levels increase with age in mice and that dietary restriction, which is known to extend the lifespan of mice, brings down NfL levels.

Abstract

Neurofilament light chain (NfL) has emerged as a promising blood biomarker for the progression of various neurological diseases. NfL is a structural protein of nerve cells, and elevated NfL levels in blood are thought to mirror damage to the nervous system. We find that plasma NfL levels increase in humans with age (n = 122; 21–107 years of age) and correlate with changes in other plasma proteins linked to neural pathways. In centenarians (n = 135), plasma NfL levels are associated with mortality equally or better than previously described multi-item scales of cognitive or physical functioning, and this observation was replicated in an independent cohort of nonagenarians (n = 180). Plasma NfL levels also increase in aging mice (n = 114; 2–30 months of age), and dietary restriction, a paradigm that extends lifespan in mice, attenuates the age-related increase in plasma NfL levels. These observations suggest a contribution of nervous system functional deterioration to late-life mortality.

Conclusion

While it’s not clear how well these findings will hold in younger populations, NfL seems to be a useful biomarker for age and longevity in older populations, correlating with all-cause mortality and health metrics. This strengthens the notion that nervous system functional deterioration is linked with mortality, though working out the linkage remains a topic for future research. Likewise, more work will be needed to understand how NfL differs from or correlates with other biomarkers of aging and mortality.

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Literature

[1] Kaeser SA, Lehallier B, Thinggaard M, Häsler LM; Apel A, Bergmann C, Berdnik D, Jeune B, Christensen K, Grönke S, Partridge L, Wyss-Coray T, Megel-From J, and Jucker M. A neuronal blood marker is associated with mortality in old age. Nature Aging (2021), doi: 10.1038/s43587-021-00028-4

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The Blog

Building a Future Free of Age-Related Disease

David Sinclair and Peter Attia Co-chair $200m Biotech SPAC

Managing Stress Responses to Slow Down Aging

A Summary of NAD+ and Human Aging – Part 2

Longevity Pharmacology with Dr. João Pedro de Magalhães

Binary Clock Predicts Biological Age

Video Gaming as a Geroprotective Strategy

Maximon Launches Longevity Biotech Builder

Kizoo Provides Seed Funding for Elastrin Therapeutics

Bioage Clinical Trial for Unexplained Anemia of Aging

A Summary of NAD+ and Human Aging – Part 1

The Dog Aging Project Is Ready for Takeoff

We interviewed you about DAP back in 2018. Maybe you can walk us through the progress you have made. Where does it stand now?

You told us back in 2018 about the rapamycin trial coming up. What is the situation on that front?

Will you be accounting for differences between male and female dogs?

What about breed differences? Do you expect any problems there?

Where do we stand with rapamycin in general? Has it been living up to the expectations?

In the previous interview you gave us, you pointed at insufficient funding as the main problem that hampers progress in the longevity field. Do you think this is still the case, or maybe we’ve already seen some commercialization of the field?

On the NIH side, the tide is starting to turn as well. Do you feel it?

I assume that you are doing research apart from the Dog Aging Project. Would you like to tell us what you are working on?

Rejuvenation Roundup February 2021

Digital Health Company Bold Lands $7 Million

Measuring Age With a Bloodborne Neural Protein

About Us

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The Blog

Building a Future Free of Age-Related Disease

We interviewed you about DAP back in 2018. Maybe you can walk us through the progress you have made. Where does it stand now?

You told us back in 2018 about the rapamycin trial coming up. What is the situation on that front?

Will you be accounting for differences between male and female dogs?

What about breed differences? Do you expect any problems there?

Where do we stand with rapamycin in general? Has it been living up to the expectations?

In the previous interview you gave us, you pointed at insufficient funding as the main problem that hampers progress in the longevity field. Do you think this is still the case, or maybe we’ve already seen some commercialization of the field?

On the NIH side, the tide is starting to turn as well. Do you feel it?

I assume that you are doing research apart from the Dog Aging Project. Would you like to tell us what you are working on?

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