BioAge Labs Announces Multi-Year Collaboration with Novartis

Date Posted: December 18, 2024

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BioAge Labs Announces Multi-Year Collaboration with Novartis

BioAge Labs, Inc. (“BioAge”), a clinical-stage biopharmaceutical company developing therapeutic product candidates for metabolic diseases by targeting the biology of human aging, today announced a multi-year research collaboration with Novartis. The collaboration aims to identify and validate multiple novel therapeutic drug targets by investigating the biological mechanisms that drive diseases related to aging and mediate the beneficial effects of physical exercise.

“Our platform, built on extensive longitudinal human longevity data, has allowed us to identify promising therapeutic pathways with significant potential to improve health outcomes,” said Kristen Fortney, CEO and co-founder of BioAge. “This collaboration with Novartis showcases the value of our platform and expands our capacity to discover and develop novel targets based on the insights from our data.”

The collaboration will leverage BioAge’s extensive proprietary human longevity datasets and Novartis expertise in exercise biology. BioAge’s proprietary discovery platform is based on exclusive access to longitudinal human aging cohorts followed for up to 50 years, combining detailed health records and functional measurements. Applying advanced analytics and machine learning techniques to this rich dataset enables BioAge to identify determinants of healthy lifespan, providing an engine for therapeutic discovery and development.

“We are excited to collaborate with BioAge, applying their human longevity data together with our scientific expertise in the biology of physical exercise to discover novel therapeutic targets,” said Michaela Kneissel, Global Head of Diseases of Aging and Regenerative medicine (DARe) at Novartis Biomedical Research. “By exploring the intersection of human aging biology and the biological drivers of the beneficial effect of physical exercise, we aim to bring forward novel treatment options for diseases related to aging.”

“The collaboration between Novartis and BioAge underscores the growing recognition that unraveling the biology of aging is a powerful approach to treating disease,” said Peng Leong, PhD, MBA, CBO and Head of Brain Aging at BioAge. “This collaboration represents a significant opportunity to accelerate our development of a broad portfolio of transformative therapies targeting novel mechanisms identified by our platform, dramatically expanding our therapeutic reach and benefiting patients across multiple indications.”

Under the terms of the agreement, BioAge will receive upfront payments and research funding of up to $20 million, plus up to $530 million in future long-term research, development, and commercial milestones. Novartis and BioAge each have the right to advance novel targets discovered under the collaboration and are each eligible to receive reciprocal success milestones and tiered royalties.

About BioAge Labs, Inc.

BioAge is a clinical-stage biopharmaceutical company developing therapeutic product candidates for metabolic diseases by targeting the biology of human aging. BioAge’s lead product candidate, azelaprag, is an orally available small molecule agonist of APJ that was observed to promote metabolism and prevent muscle atrophy on bed rest in a Phase 1b clinical trial. BioAge is also developing orally available small molecule brain penetrant NLRP3 inhibitors for the treatment of diseases driven by neuroinflammation. BioAge’s preclinical programs, based on novel insights from the company’s discovery platform built on human longevity data, address key pathways in metabolic aging.

Forward-looking statements

Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute “forward-looking statements.” These statements include, but are not limited to, statements relating to anticipated preclinical and clinical development activities, timing of announcements of clinical results, trial initiation, and regulatory filings, potential benefits of azelaprag and the Company’s other product candidates and platform, the potential and timing of future milestone payments under the agreement with Novartis, and potential market opportunities for azelaprag and BioAge’s other product candidates. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: BioAge’s ability to advance its product candidates, the timing and results of preclinical and clinical trials, the Company’s ability to fund development activities and achieve development goals, the Company’s ability to protect intellectual property, the Company’s commercial collaborations with third parties, the potential impact of global business or macroeconomic conditions, and the sufficiency of BioAge’s cash, cash equivalents and investments to fund its operations, and other factors discussed under the heading “Risk Factors” section of documents BioAge files from time to time with the Securities and Exchange Commission. Any forward-looking statements contained in this press release are based on the current expectations of BioAge’s management team and speak only as of the date hereof, and BioAge specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise.

Contacts

PR: Chris Patil, media@bioagelabs.com

IR: Elena Liapounova, ir@bioagelabs.com

Partnering: partnering@bioagelabs.com

Web: https://bioagelabs.com

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Date Posted: December 18, 2024

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Lower Rates of Epigenetic Aging in Olympic Champions

A recent investigation into Hungarian Olympic champions suggests slower epigenetic aging and differences in gene methylation patterns between champions and non-champions [1].

Exercising your way to longevity

Exercise seems to be the best lifestyle factor to slow aging and alleviates many aging-associated diseases and molecular changes.

We have previously reported that exercise positively impacts cognition in older people, has protective effects against motor nerve degeneration, lowers the activity of the inflammatory SASP in the elderly, and increases levels of autophagy, a cellular process with longevity-promoting effects. Previous research has also shown that exercise may act as a natural senolytic.

Most of this research describes interventions in which participants exercise at moderate levels. However, some people, particularly professional athletes, train almost daily for several hours. Those athletes often start intense exercise at a young age. Such long-term interventions started early might have a long-term impact on the epigenome, which chemically controls how genes are expressed.

One such alteration is DNA methylation. Multiple epigenetic clocks utilize methylation patterns to assess the rate of aging, and exercise is known to impact their results. While the benefits of moderate exercise have been thoroughly documented, the authors of this study were interested in the impact of high amounts of it, such as by professional athletes that have achieved Olympic medals.

Olympians’ decreased age acceleration

The researchers recruited 59 Hungarian Olympic gold medalists, 10 females and 49 males, and 329 controls, 161 female and 168 male. The control group consisted of 205 master rowers, with the remainder being healthy, untrained volunteers. The age range of the study participants was between 24 and 101 years. The Olympians’ mean age was 53 for females and 52 for males. The control group’s mean age was 60 for females and 58 for males.

The researchers measured the epigenetic age of the participants using multiple epigenetic clocks. While there were some differences between the clocks, the authors highlight the Hannum and Skin-Blood clocks, which indicated significantly decreased epigenetic age acceleration in female Olympic champions compared to female non-champions. Similarly, when male Olympic champions were compared to male non-champions, the Skin-Blood and PhenoAge clocks showed significantly decreased age acceleration.

The researchers also estimated telomere length from methylation data and “found that the age-adjusted DNAm telomere length increased in Olympic champions compared to the non-champions for both sexes.”

Sex-specific age acceleration patterns

Athletes are usually at the peak of their performance when they win medals. Therefore, the researchers divided the athletes into two groups: “Olympic champions who earned any medal in Olympic games, World, European, or League Championships less than 10 years before blood sampling,” referred to as ‘recent medalists’, and the second group, who won medals more than 10 years before blood sampling and are referred to as ‘past medalists.’

Comparing the age acceleration in those two groups revealed sex-specific differences. For male champions, the researchers observed significantly lower epigenetic age acceleration in the recent medalists’ group compared to the past medalists’ group, as indicated by several clocks.

The DNAmFitAge and GrimAge clocks showed the opposite for females. Female champions had significantly higher epigenetic age acceleration in the recent medalists’ group compared to the past medalists’ group.

The sport matters

Different sports can impact the body differently. The researchers analyzed age acceleration to analyze the impact of different sports disciplines on Olympic champions; however, it was done only for the disciplines represented by at least three champions. They only found differences among the male athletes. For males, the age acceleration “in wrestling was significantly higher compared to that of gymnastics, fencing, and water polo according to some epigenetic aging clocks.”

The authors point out that their sample size in this analysis was small, so they do not draw strong conclusions, but they speculate factors such as different types of training, nutrition, weight-controlling methods, and education (in this study group, fencers and water polo players held higher levels of education than wrestlers) might contribute to the observed results.

Those results seem to go in line with the results of a study on which we previously reported, which analyzed associations between professional sports and longevity. In that study, the researchers reported gymnastics and fencing to be among the highest-scoring sports for life extension in males (8.2 and 6.6 years, respectively). Water polo still had a quite high positive impact (3.6 years), while the effect of wrestling was very minor (0.5 years).

The cellular level

The researchers also investigated the data on a more granular level by analyzing methylation levels of CpG sites associated with the promoter region of each gene. They identified the top 20 differently methylated genes between champions and the control group.

First, they analyzed hypomethylated genes. The DNA in hypomethylated regions is more accessible for transcription factors, which can encourage gene expression. The Olympic champions’ most hypomethylated genes were involved in regulation of complex cellular signaling, transfer processes, differentiations, and force generation.

On the other hand, hypermethylation leads to gene silencing. The genes hypermethylated in Olympic champions were involved in tumor suppression, telomere maintenance, fertility, and cellular signaling.

Long-lasting effects

The researchers discuss that their results suggest that exercise impacts long-term epigenetic alterations. They highlight previous research that shows that lifestyle choices during puberty or adolescence impact adult DNA methylation patterns [2, 3]. They further suggest that as Olympic champions often start their training young and continue into adolescence, this positively impacts their DNA methylation even after they have stopped their training routines as adults.

Yes I will donate❤️

Literature

[1] Radák, Z., Aczél, D., Fejes, I., Mozaffaritabar, S., Pavlik, G., Komka, Z., Balogh, L., Babszki, Z., Babszki, G., Koltai, E., McGreevy, K. M., Gordevicius, J., Horvath, S., & Kerepesi, C. (2024). Slowed epigenetic aging in Olympic champions compared to non-champions. GeroScience, 10.1007/s11357-024-01440-5. Advance online publication.

[2] de Vocht, F., Suderman, M., Tilling, K., Heron, J., Howe, L. D., Campbell, R., Hickman, M., & Relton, C. (2018). DNA methylation from birth to late adolescence and development of multiple-risk behaviours. Journal of affective disorders, 227, 588–594.

[3] Kankaanpää, A., Tolvanen, A., Heikkinen, A., Kaprio, J., Ollikainen, M., & Sillanpää, E. (2022). The role of adolescent lifestyle habits in biological aging: A prospective twin study. eLife, 11, e80729.

Date Posted: December 17, 2024

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A Senolytic Approach to Faster Wound Healing

Researchers have published in Aging their findings that a senolytic compound accelerates wound healing in aged mice when it is administered before the wound occurs.

A well-known laboratory senolytic

While some senescent cells have been found to have a beneficial effect on wound healing [1], the increase in cellular senescence with age has been suspected of slowing down healing instead [2]. ABT-263 is a senolytic compound that has been commonly researched in the laboratory, and previous work has found that it reduces some of the signs of skin aging [3]. Therefore, this research was a straightforward logical progression, although some of the findings were counterintuitive.

In their first experiment, the researchers treated the skin of 24-month-old mice with either DMSO, a compound that helps to infuse other compounds into the skin, by itself (control group) or a combination of DMSO and ABT-263 (treatment group) for five days. This corroborated other research showing ABT-263’s senolytic effects, as the treatment group’s skin had less of the senescence markers p16 and p21 along with the senescence biomarker SA-β-gal. These findings only applied in an aged population, as they were not replicated in 2-month-old mice.

Intriguing but positive effects

Despite these senolytic effects, the treatment increased, not decreased, inflammation as a whole. Compared to DMSO alone, 24-month-old mice that received the treatment had significantly increased macrophage infiltration of the skin, and there was an elevation in neutrophils as well. However, they also had significanty fewer T cells.

The researchers hypothesize that this is due to mass senolysis: the senescent cells, dying in large quantities, release their contents into the area, and these damage-associated molecular pattern (DAMPs) spur macrophages to clean up their remains. This is in line with previous work showing that transient inflammation may accelerate wound heaing [4].

The researchers note that ABT-263 is known to spur senescent cell removal (senolysis) by inhibiting the Bcl-2 protein family, which prevents cells from dying by apoptosis. Those findings were replicated in this study: Bcl2 was significantly upregulated in the treatment group.

Interestingly, some but not all of the SASP, which is secreted by senescent cells, was upregulated by ABT-263 compared to controls. A database of SASP genes expressed in mice did not find any significant differences as a whole. However, many inflammatory factors, including interleukins and chemokines, that previous work had found to be associated with the SASP [5] were very significantly upregulated by ABT-263.

Most critically for this study, genes related to wound healing were also significantly upregulated by the treatment. The expression of genes related to blood vessel formation, collagen synthesis, and cellular proliferation were increased alongside inflammation and wound healing more generally.

Pre-treating aged mouse skin with ABT-263 before a wound was inflicted yielded fruitful results. Here, 24-month-old mice were treated with either the DMSO control or the active combination for five days before a one centimeter-wide patch of skin was cut away. By day 15, the treatment’s effects were statistically significant: a third of the treatment group was considered to be totally healed, while none of the control group met this threshold. By day 21, the treated mice had no open wounds remaining, while some of the untreated mice still had visible injuries.

Is a topical approach best?

The researchers note some differences between their approach, which only applied ABT-263 to small patches of skin, and previous work that introduced ABT-263 to mice more systemically. There was a risk of a loss of neutrophils (neutropenia), but this topical approach increased neutrophils instead. Furthermore, the pretreatment-only approach they used was intentional; they noted the role of senescent cells in wound healing and the potential risk in removing them once healing had begun.

Therefore, it is unlikely that ABT-263 will ever be employed as an after-the-fact wound treatment. However, it holds promise for surgery, which involves pre-planned wounds. If older people with more senescent skin are given topical ABT-263 before these sorts of medical interventions, such a treatment could potentially reduce their recovery time and encourage healthy collagen production; however, it remains to be seen if the murine findings of this study apply to human beings.

Yes I will donate❤️

Literature

[1] Kim, H., Jang, J., Song, M. J., Kim, G., Park, C. H., Lee, D. H., … & Chung, J. H. (2022). Attenuation of intrinsic ageing of the skin via elimination of senescent dermal fibroblasts with senolytic drugs. Journal of the European Academy of Dermatology and Venereology, 36(7), 1125-1135.

[2] Andrade, A. M., Sun, M., Gasek, N. S., Hargis, G. R., Sharafieh, R., & Xu, M. (2022). Role of senescent cells in cutaneous wound healing. Biology, 11(12), 1731.

[3] Kita, A., Yamamoto, S., Saito, Y., & Chikenji, T. S. (2024). Cellular senescence and wound healing in aged and diabetic skin. Frontiers in Physiology, 15, 1344116.

[4] Naik, S., Larsen, S. B., Gomez, N. C., Alaverdyan, K., Sendoel, A., Yuan, S., … & Fuchs, E. (2017). Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature, 550(7677), 475-480.

[5] Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual review of pathology: mechanisms of disease, 5(1), 99-118.

Date Posted: December 16, 2024

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Encouraging Hair Growth by Reducing Senescence

In Aging Cell, researchers have described how to improve the hair growth potential of stem cells and organoids by reducing cellular senescence.

The quest for a true stem cell hair treatment

There has been a substantial amount of previous work in restoring hair follicle growth by culturing dermal papilla cells (DPs), which are the mesenchymal stem cells (MSCs) responsible for hair growth within follicles [1]. However, utilizing these cells to treat patients has proved unexpectedly difficult: outside the context of an active hair follicle, these cells quickly forget what they’re supposed to do and their hair growing ability swiftly declines [2].

Furthermore, unlike with rodent cells, repeated passages of human DPs cause them to lose potency. While there have been multiple attempts to restore this through various methods, such as conditioned media [3] and implantation into an extracellular matrix [4], such approaches have only been documented to work on early-passage cells.

The researchers attribute some of this decreasing capability to a rise in cellular senescence, as senescent cells and their secreted compounds (SASP) have been listed as causes of dysfunction [5] and removing them has restored hair in a mouse model [6]. In a living animal, senescent cells are naturally cleared, such as by the immune system; however, this mechanism doesn’t exist in cell cultures.

Hair cells become senescent quickly in culture

In their first experiment, the researchers extracted and cultured DPs and dermal fibroblasts (DFs) from the same donor. While those cells don’t grow hair, they are well-studied in the context of senescence and share a common progenitor with DPs.

The DPs rapidly became more senescent than the DFs, even from the very first cellular passage, according to the well-known biomarker SA-β-Gal. The DPs also rapidly became senescent according to several other markers, including a loss of proliferation and an increase in p16 and p21.

The rapid predominance of senescent cells in DP culture also meant a sharp increase in SASP factors, including the inflammatory factors IL-6 and IL-8. Compounding the problem, cells that were exposed to these inflammatory factors were found to have their own productive abilities suppressed. An RNA analysis confirmed these findings, showing a marked rise in SASP-related signaling among these cultured cells.

A senolytic solution

Senolytics, drugs that remove and destroy senescent cells, may or may not be advisable for living organisms, as senescence is required in some situations. However, in cell cultures, none of those concerns apply.

At passage 3, the researchers administered dasatinib and quercetin, a well-studied senolytic combination, to a population of DPs. This approach was effective: the senescent cells were rapidly killed off. Interestingly, many of the remaining cells entered into a quiescent state, as measured by the biomarker p27; however, quiescent DPs can be woken up and encouraged to fulfill their function, while senescent DPs cannot. As expected, senolytic treatment also removed the influence of the SASP, significantly reducing such SASP factors as IL-6 and the downstream effects.

Intrigued, the researchers continued their work by first applying senolytics to DPs at passages 2, 3, and 4, and then using them to create 500 spheroids that each contained 2000 human DPs and a million mouse keratinocytes. They then implanted these spheroids into the backs of hairless mice. Compared to a non-senolytic control group, the senolytic-applied DPs were far more effective at growing hair. Unfortunately but expectedly, the DPs that were taken at passage 2 were more effective than similar cells taken at passages 3 and 4, demonstrating that while senolytics are effective, they are not a complete solution for later-passage DPs.

These results were recapitulated in an experiment involving cultured human skin. A million human DPs and two million human DFs were seeded in wells of collagen. The cells that were exposed to senolytics were found to grow keratin and hair follicle structures, but the control group that had not been exposed to senolytics did not.

While the researchers acknowledge that their work is incomplete and that they still do not have a readily available treatment for hair loss, they hold that senolytics are key in overcoming one of the major hurdles associated with this line of work. Further research will need to be done to create artificial human skin that can grow hair in the same way that the skin of living, healthy people can.

Yes I will donate❤️

Literature

[1] Leirós, G. J., Kusinsky, A. G., Drago, H., Bossi, S., Sturla, F., Castellanos, M. L., … & Balañá, M. E. (2014). Dermal papilla cells improve the wound healing process and generate hair bud-like structures in grafted skin substitutes using hair follicle stem cells. Stem cells translational medicine, 3(10), 1209-1219.

[2] Ohyama, M., Kobayashi, T., Sasaki, T., Shimizu, A., & Amagai, M. (2012). Restoration of the intrinsic properties of human dermal papilla in vitro. Journal of Cell Science, 125(17), 4114-4125.

[3] Abreu, C. M., Cerqueira, M. T., Pirraco, R. P., Gasperini, L., Reis, R. L., & Marques, A. P. (2021). Rescuing key native traits in cultured dermal papilla cells for human hair regeneration. Journal of Advanced Research, 30, 103-112.

[4] Liu, Z., Huang, J., Kang, D., Zhou, Y., Du, L., Qu, Q., … & Miao, Y. (2023). Microenvironmental reprogramming of human dermal papilla cells for hair follicle tissue engineering. Acta Biomaterialia, 165, 31-49.

[5] Shin, W., Rosin, N. L., Sparks, H., Sinha, S., Rahmani, W., Sharma, N., … & Biernaskie, J. (2020). Dysfunction of hair follicle mesenchymal progenitors contributes to age-associated hair loss. Developmental cell, 53(2), 185-198.

[6] Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., … & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147.

Date Posted: December 13, 2024

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Why Research Teams Should Email XPRIZE Healthspan Now

With the deadline for submissions just around the corner, Jamie Justice, Executive Director of XPRIZE HealthSpan, explains to researchers still on the fence why they should contact her team now but also why missing the deadline is not the end of the world.

XPRIZE Foundation has been making history for 30 years with dozens of prizes in various fields, from space exploration to climate research. Symbolically, XPRIZE Healthspan, announced last year, is the biggest one yet, with a whopping $101 million in prize money that can go a long way in advancing the science of longevity.

We have previously discussed XPRIZE Healthspan with XPRIZE founder Peter Diamandis and with Hevolution Foundation CEO Dr. Mehmood Khan. However, when it comes to the nitty-gritty of this giant enterprise, Jamie is the one to talk to, which we did.

Where does XPRIZE Healthspan stand as of now?

We’re just over one year since our launch. We spent our first six months in what we call the public comment period, getting advice from investigators worldwide. Then, we posted our competition guidelines and opened for primary registration – the primary chance for teams to submit qualifying submissions to advance into the competition.

Primary registration closes on December 20th officially, but we have opportunities for teams to come in later. They may not be able to advance through our first judging, but there are still opportunities to get involved, whether as a competitor or through our partnership ecosystem.

Just to clarify: a team will still be able to participate if they submit after December 20th, correct?

They will. Teams submitting after December 20th can still be considered as competitors. However, they might miss our first judging round, after which the top 40 teams will receive $250,000 each to help them advance in the competition. That’s what the December 20th deadline is really for – Milestone One judging. If a team wants to be considered for this, they need to communicate with us by that deadline so that their application can be reviewed in time. But missing this deadline doesn’t preclude teams from entering the competition; they just might not be eligible for these initial monetary awards.

We’re actually going to allow discretionary late registrations all the way to 2027. We know developing the next great idea takes time, especially for those looking to translate into human clinical trials. There are barriers that people might not know if they’re ready to overcome. Maybe they have something newer in development, they’re still doing preclinical work, and they’re on the fence about competing.

We want to encourage such teams to submit now. You can still be judged, and even if you don’t make the top 40, you already have your foot in the door. At no point are we trying to gatekeep, to close people out. They just need to have an open conversation with us and submit a letter of intent to continue.

So, you are encouraging teams to reach out to you.

Yes, email us at healthspan@xprize.org – that’s our team address. Let us know if you might have a late submission. All discretionary late registrations require a conversation with us first, where we ask them to submit a letter explaining why they’ll be late. We’ll determine if there’s an opportunity to move forward. For us, it’s just a matter of timing – we’ll have to form ad hoc judging panels to ensure they can meet goals along the way.

This is a $101 million global incentivized competition. For the grand prize, teams have to show they’ve restored muscle, cognitive, and/or immune function in older adults. The therapeutic must be administered in one year or less. To win, they have to demonstrate that their therapeutic can improve function by 10, 15, or 20 years. These are personalized response thresholds that individuals in their trial must meet. And yes, I said trial – people have to use clinical trials for the finals, which start in 2026.

Right now, we’re asking teams to submit for Milestone One – bring us their idea, tell us who they are as a team, where their testing center might be, where they propose to do clinical trials or what research stage they’re at. They need to detail their therapeutic, their preclinical evidence, what they’ve already done, and ideas about how it might work. It’s a pen-and-paper submission.

The 40 semifinalists will receive funding to continue and get to attend our milestone award summit, coupled with an investor summit. That’s the real prize for making top 40 – the chance to pitch their idea and potentially receive additional funding from investors, funders, or foundations interested in this area.

We’re going to give feedback to all teams who submit. The judges will tell them if there was a gap that needed to be met: “Great application, you might consider bringing in X expertise” or “You might consider finding a clinical research organization.” This is especially valuable for teams that are on the bubble, maybe missing the top 40 but still having an opportunity to make the finals.

How many teams have already applied, and what is their geographic makeup?

We’re at a fascinating point near our deadline. Our goal was 500 teams. My initial goal was 300, but Peter Diamandis said “no, 500,” and we bartered back and forth. Now, we have 510 teams who have at least registered their interest in competing.

Not all will submit qualifying submissions – some may start the process and realize they’re not ready or withdraw. We hope they’ll at least submit something for consideration. It would be sad for those who start with us to not make this final step.

These 510 teams come from 54 countries – we’re truly global. Our top five countries are United States, Canada, China, India, Japan, and United Kingdom (tied). Beyond that, we have strong representation from South Korea, France, Australia, South Africa, Switzerland, Brazil, Denmark, Spain, Israel, Turkey – those are our top 15. This global representation across continents reflects the global interest in aging and longevity research.

What is the distribution in terms of academia versus for-profits?

Right now, about 50% of our teams are for-profit. We’re approaching 18-20% academic teams, and that number keeps increasing as we get closer to the submission deadline. We have other nonprofit research organizations and numerous student-led teams – from middle school and high school to undergraduates and graduate students leading teams together. We also have biohacker groups that don’t quite fit any category.

Do you require teams to be legal entities?

We don’t exactly require this, but within our competition guidelines, you need some sort of established entity we can write a check to if you win. How that’s structured on the team’s side, we don’t determine. Some teams are collaborations between legal entities based on memorandums of agreement. Some are actual businesses. Others are figuring out creative ways to pull it together. Some are individuals who’ll name one person as their lead.

Does the prize structure advantage certain types of teams?

It does. We’re asking teams to develop therapeutics, which requires intellectual and infrastructure background to do research. Whether they’re a company, academic group, or small nonprofit, they need facilities. Part of our questionnaire asks if they can conduct clinical trials, if they have research and clinical space. This might make it more difficult for biohacker teams without centralized locations or clinics – not impossible, just challenging.

Interestingly, while academics usually make up 20-30% of registrants, as we know from previous XPRIZEs, they’re actually more likely to make it to the finals. They have certain advantages – support structures, core facilities, or business units built into their institutions, plus existing grant mechanisms they can leverage.

Still, many of our winners are companies. Companies have the advantage of being more nimble – it’s easier for them to pivot and maybe take something from their pipeline that fits. Some academic groups may not be so positioned.

What we’re seeing is a great opportunity for academic and industry teams to merge. Such partnership teams would probably have a distinct advantage – combining the fleet-footed principles from commercial space with academic resources and scientific expertise across both sectors could be a winning combination.

Can you give any advice to the competitors?

I think I did – contact us! If you’re on the fence, try it. Do it. This will be one of those competitions that if you don’t try, you won’t know. If you’re thinking, “Oh my gosh, this qualifying submission is 12 pages” – make it shorter if you don’t have the time but put something together and try.

We have templates online, guidance documents, our email address, a Slack channel we’re monitoring almost 24/7 right now. Not many on my team are sleeping well these days, and we don’t plan to through December 20th. We’re really here for our teams. That’s the biggest advice I can give anyone – just try it. Don’t miss it by sitting on the fence wondering if your idea is good enough.

Can you expand on your endpoints? Making it about restoring function was an interesting decision.

We had to pick endpoints – muscle, cognitive, and immune – working with an endpoints committee to define measures that are simple, understandable, feasible to measure in trials, and show great potential. We established the criteria with our working group and advisory boards (this isn’t published yet, but there will be a scientific paper).

Those criteria consider several factors for each measure: face validity (does a measure of muscle power relate to muscle function?); relevance to biological aging (if the system is disrupted in animal models, is it fundamentally linked to biology?); association with chronological age across multiple populations; link to mortality risk, disease risk, and disability; longitudinal change over time; and responsiveness to intervention.

The hardest criterion for anyone to meet is showing that if it changes with intervention, is it a mediator of change in those events? No one has that because we don’t have enough clinical trials. For measures that haven’t met all criteria, like immune function, we had to decide: do we kick that measure out, or do we use the prize competition process as the means to actually develop the measures?

We’re filling in gaps along the way. What impact points do we need? What datasets are we missing? What consensus factors does the field need? We can use the prize to build momentum and pull people along – refining endpoints, getting measures, determining criteria, developing regulatory frameworks.

Our approach to trial design is particularly interesting. Traditionally, trials compare group averages – treatment group versus control group. That’s great for trials, and we love randomization, but at early stages, it can be challenging. We don’t take therapeutics based on the mean. Yes, maybe this group average is different than that group average, but is it meaningful?

What you’re saying is that the prize will advance the field regardless of the results, for instance, by improving our understanding of how to measure aging.

Yes, the prize gives the longevity field a chance to define what’s meaningful. What do we as scientists, experts, and drug developers think is important? The magnitude of effects we’re choosing – 10 years, 20 years – these are just numbers until we build references behind them. How do we do that?

What is meaningful for a clinician when treating an individual? Clinicians aren’t prescribing to the average, they’re prescribing to someone specific. After that person started the intervention, we need to look at individualized response over time. Did this person improve relative to themselves?

That’s not necessarily how we think in early stages of translation, but it’s how we need to think about applying these therapeutics. We have a chance with this prize to develop those references and consider what matters to individuals, clinicians, stakeholders, and companies that might acquire or de-risk larger trials.

For Milestones one and two, we left a lot up to our teams, but for finals, some things are fixed. We’ll have a data coordinating center, and we feel strongly about the personalized response threshold approach. This requires a particular structure – teams need multiple baseline points before randomization to either drug or control. They can do whatever they want during their intervention period, but we need multiple follow-up points.

Those multiple baseline points before randomization are crucial because we need to know how variable people are in their day-to-day. We need a solid baseline because that person becomes their own control group. When setting thresholds, we’re looking at how they compare to themselves, not to somebody else.

Some parts are absolutely a work in progress – like the biomarkers for immune function. I’ve been on a warpath for a year about this and will continue. By the time we open for finals, I want a biomarkers bonus prize.

A bonus prize is an interesting idea, especially for developing biomarkers of aging, which is a pressing need in our field. This brings me to the question: is the prize open to additional sponsors?

Absolutely. We hope to announce soon an additional sponsor helping with operations. I’d love to have an additional sponsor help put together a biomarker bonus prize. It doesn’t need to be $100 million. It just needs to be enough to get people to chase it. Think of how many people we have to sign up for one-year trials. A biomarker prize would be asking for much less.

We also have opportunities for sponsors to help with marketing, events, documentaries. One big thing XPRIZE does is democratize science. We want public engagement. We’re looking for opportunities for events and outreach, especially to groups that don’t typically compete in prizes like this – student groups or teams from lower or middle-income countries that might not have the resources of larger universities and countries in the West.

There are many sponsorship opportunities, if not through XPRIZE, then to individual teams and groups doing the work. If anybody’s interested in making those contributions, we’d be happy to help make connections and get people engaged. Teams need it. The field needs it.

You seem fired up about this project. What does it mean to you personally?

I am hugely excited about this. I was about to turn in my promotion materials when I got this call from XPRIZE to lead the prize that aligned with my scientific work. It was the biggest bet of my life.

It seemed like a huge risk, relying on the global community to come up and support it. We’re decentralizing not just any science, but the science of longevity. It’s a wild concept – crowdsourcing the greatest innovations that we think will change how we live and age.

To go through this process over the last year and have huge public reception, to have 500 teams sign up, to get sponsors to sign on and have partners like lifespan.io joining us – it’s actually working. We’re just at the start line, but we have people who’ve shown up with us. It’s remarkable.

I was on a call this afternoon with Dr. Lauren Pierpoint, who’s a biostatistician and epidemiologist. She similarly took a bet on XPRIZE, leaving her career. We were going through team submissions and metadata, and she just started giggling and said, “Jamie, it’s working.” We’re just at the start – there’s so much left to do in the next six years – but that we could at least get to this stage speaks volumes.

We received some information after this interview was completed:

XPRIZE Healthspan closes primary registration on Friday, 20 December 2024, but we are extending the deadline for Qualifying Submission upload until 31 December 2024.
This means teams need to go enter their team and contact information on our registration website by 20 December (https://pop.xprize.org/prizes/healthspan/overview) . Teams with an active registration profile will be able to access the portal and complete their ~12-pg Qualifying Submission until the platform closes at 7pm PT on 12/31/24. But teams who wait are at their own risk as our offices are not staffed over the Holidays; there is no guarantee of technical or scientific support for Qualifying Submissions after 20 December.

Yes I will donate❤️

Date Posted: December 12, 2024

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LongGame Venture Capital Fund Officially Launched

Crypto investor and founder Will Harborne will lead a new enterprise aimed at funding and supporting groundbreaking longevity technologies.

From crypto to longevity

The burgeoning field of longevity biotech is about to have a new player. Like many recent enterprises, such as Brian Armstrong’s NewLimit, this one is driven by someone coming from the crypto field.

A team led by Will Harborne, a leading crypto investor and founder known for his work with Bitfinex, rhino.fi, and ZKV, has announced today the launch of LongGame, a new venture capital fund designed to invest in groundbreaking longevity biotech companies. The fund is actively fundraising, with the goal set at $40 million.

At a time when many venture capital funds are wary about “high risk, high reward” technologies that may take years and decades to mature, LongGame is going all in, as evident already from its name. The fund proudly touts its “radical focus” and promises that all its investments will “target therapies with the potential to increase human lifespan by 10+ years and ideally significantly more.”

The philosophy and the team

Despite this spirit of disruptive boldness, LongGame’s announced investment priorities are not necessarily revolutionary: stem cell therapies, gene editing, and senolytics. While the first two have a lot of untapped potential, many researchers think that the impact of senolytics on lifespan is more likely to be limited. It remains to be seen whether LongGame will venture into other radical territories such as organ and tissue replacement.

The fund also plans to leverage its crypto roots by “exploring potential crossovers between biotech and crypto in the newly emerging DeSci space.” Decentralized science (DeSci) is indeed an exciting new paradigm aimed at streamlining and democratizing research and development while also fixing some obvious flaws in the current system of incentives.

LongGame boasts an impressive team. Chloe Northcott, formerly at Geometry, will serve as Chief Operating Officer, while Dr. Manish Chamoli, hailing from the famed Buck Institute for Research on Aging, will assume the role of Chief Scientific Officer. Sebastian Brunemeier, General Partner at Healthspan Capital, will join as a special advisor. “The team at LongGame are truly mission-driven and laser-focused on Long-Bio, entering the sector at a time when the field is at a major inflection point,” he told lifespan.io.

“Longevity is the next frontier of innovation, and just as we’ve seen crypto disrupt traditional finance, we believe that longevity biotech will do the same for health,” said Harborne, Founder and Managing Partner of LongGame. “Our goal is to fund therapies that do more than just extend life; we’re looking for solutions that radically expand the healthy human lifespan—by 30 years or more. We’re tackling the root causes of aging, not just the symptoms.”

Leading by example

Will leads by personal example: inspired by longevity pioneers like Bryan Johnson and his Blueprint program, he has transformed his own life in pursuit of life extension. He follows a precision health regimen that includes a supplement stack, exercise, and other practices to optimize physical and mental performance as well as a lot of testing beyond routine bloodwork. Will realizes, however, that lifestyle changes can only take him so far, and to go beyond this, major advancements in our understanding and manipulation of aging biology are required.

Will says that his commitment to longevity is not just a personal journey, but a scientific exploration into the future of human health. He also cares about future longevity therapies being widely available: “We want to ensure that these life-extending therapies are accessible to the masses, not just the wealthy. Longevity shouldn’t be just about helping the wealthy live longer but about helping the whole of society have significantly longer and healthier lives.”

We asked Will a few more questions in an exclusive blitz interview:

What is the new fund’s “secret formula” for success?

Secret formula is to combine our experience as founders in industries which are as highly uncertain as longevity biotech or potentially even more so (like crypto), with super high-quality scientific due diligence and a focus on commercialisability.

Many venture funds are cautious about the long-term and uncertain nature of investing in longevity biotech. However, LongGame seems to embrace it, even in its name. Are you really in this for the long haul?

We are committed to the long haul because solving aging is not a quick endeavor. Our LPs are motivated and fully aligned with this mission as well as with the potential for significant returns. This first fund serves as a precursor to a larger follow-up fund, where we aim to invest at later stages. However, our immediate priority is to demonstrate that early-stage longevity biotech can deliver returns that justify the inherent uncertainty and risk.

While investing in this space is undoubtedly challenging, it also presents immense opportunity. Many companies struggle to raise capital due to the long-term and uncertain nature of the field, with all longevity biotech ventures often painted with the same broad brush. However, not all companies are equal in their paths to commercialization. We see a unique opportunity to identify and support those with stronger short-term commercial prospects, helping them navigate uncertainty more efficiently.

What are your predictions for the near future of longevity biotech, particularly in light of recent setbacks like BioAge discontinuing its Phase II trial? Are we entering “the valley of death”?

We certainly don’t see this as the valley of death, and setbacks in all areas of biotech are common, particularly at clinical trials. Although this has not yet filtered through to clinical trial outcomes due to the long time frames involved, we see the next 10 years as a major engineering unlock (following research breakthroughs). Particularly when combined with progress in all areas of AI, and overlap to biotech, we see the potential for a longevity biotech golden era ahead, with successes leading to a positive feedback loop.

How do you intend to measure life extension outcomes (e.g., +10 years, +30 years)?

That’s very hard to do, and until we get the first approved aging interventions to market, any numbers will be predictions and likely wrong. Eventually, statistical evidence will emerge, and we are looking for life extension in healthy humans, not in obese or inactive populations.

Yes I will donate❤️

Date Posted: December 11, 2024

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Extending Monkeys’ Reproductive Span With Stem Cells

An investigation into transplanting human embryonic stem cells (hESC)-derived MSC-like cells (M cells) into the ovaries of cynomolgus monkeys suggests an extension of female reproductive span accompanied by a reduction in senescence-associated processes, such as inflammation, fibrosis, oxidative damage, and apoptosis [1].

Increasing healthspan by delaying menopause

Aging of the female reproductive system precedes aging of other systems, resulting in women living one-third of their lives after menopause [2]. Menopause results not only in the cessation of reproduction but is also associated with health problems such as osteoporosis [3], cardiovascular problems [4], and neurodegenerative diseases [5]. Therefore, delaying menopause could allow women to live longer, disease-free lives, and so the authors chose stem cell transplantation as a possible therapeutic approach to delay ovarian aging and increase the reproductive span.

Perimenopausal Chinese women’s ovarian reserve

Female reproductive aging is tightly linked to ovarian reserve, which is measured by the number of primordial follicles. The ovarian follicle is a cellular structure that releases an egg that can be fertilized. The follicle’s oocyte is surrounded by granulosa cells (GCs) and theca cells (TCs).

A female’s ovarian reserve is established while still in her mother’s womb. Once a woman enters puberty, every menstrual cycle draws from the reserve of primordial follicles. This process slowly diminished the ovarian reserve, leading to menopause.

Multiple studies have analyzed ovarian reserve decline. However, none has analyzed the ovarian reserve of Asian women. Since there is variability among different demographics regarding the age at menopause, there are also likely to be differences in ovarian reserve decline among different demographic groups. To address that, those researchers analyzed the ovarian reserve in Chinese females.

The researchers collected 28 ovaries from 26 Chinese women between 35 and 52 years old and counted the follicles in the stained, thin ovarian sections.

In the youngest group of females, aged 35-39, the average number of primordial follicles per ovary was 11,098. This number decreased with age. In females aged 40-44, it was 6,728; in the 45-49 group, it was 1,019, and there were only 151 in the oldest group aged 50-52. On the other side, the diameters of oocytes and oocyte nuclei of primordial follicles were similar between females of different ages.

The authors also observed the primordial follicles to develop into primary and secondary follicles in perimenopausal women. However, the number of both decreased with age. They conclude that the primordial follicles in perimenopausal women could still develop into growing follicles.

Alleviating ovarian aging with stem cells

Mesenchymal stem cell (MSC)-based therapy has shown potential in reversing ovarian aging and recovering fertility in animal models and women suffering from premature ovarian insufficiency [6-9]. However, this approach has some limitations.

hESC-derived M cells resemble MSCs but can overcome some of MSCs’ limitations, such as manufacturing at scale. Research has also discovered that they also have more potent immunomodulatory and anti-fibrotic functions [10].

With the aim of testing “the safety and efficacy of M-cell transplantation in ameliorating human physiological ovarian aging,” the researchers have chosen naturally aging cynomolgus monkeys as their model systems, since ovarian aging shares plenty of similarities between monkeys and humans.

The authors selected ten perimenopausal monkeys and divided them into two groups: three as controls and seven in the treatment group. They injected the monkeys’ ovaries with M cells twice, one month apart, and followed up for eight months. The results suggested the safety of the treatment, as no acute inflammation or malignant diseases were observed.

A comparison of treated and untreated monkeys showed some positive impacts of the treatment. The researchers observed significantly larger ovarian diameters and thicker endometria in the treated group. Sex hormone levels were also positively impacted – estradiol levels were higher than control in 6 and 8 months post-treatment check-ups and progesterone remained at higher levels in treated monkeys, while in the control group, progesterone levels decreased during the follow-up period.

The researchers also tested the impact of M-cell treatment on follicle development. Assessment of the number of follicles showed increased numbers of growing follicles in the treated group compared to the control group, suggesting increased fertility potential following the treatment.

The treatment also alleviated ovarian aging, as the examination of ovaries showed decreased fibrosis, higher numbers of proliferative GC cells, which are essential for follicle development, and reduced DNA damage markers in GC cells in the treated group compared to the control.

Extending reproductive span

While the changes in molecular processes and hormonal levels are important for testing ovarian aging, the ultimate test of whether the treatment works is whether the monkeys can conceive a child.

In the initial test, the researchers injected monkeys with recombinant hormones to stimulate follicle growth and egg production. Two monkeys from the control group that were injected with hormones didn’t yield oocytes. Four monkeys from the treatment group injected with hormones yielded between 1 and 33 oocytes. Two monkeys produced mature oocytes that were collected for intracytoplasmic sperm injection (ICSI) and successfully fertilized. Out of those, two fertilized eggs developed to the blastocyst stage.

Monkeys were also allowed to breed for two months to test the possibility of natural conception. One treated monkey got pregnant and delivered a healthy, full-term baby. The baby is around three years old and still healthy, similar to the babies delivered by younger monkeys.

Molecular mechanism

The molecular mechanism behind the recovery of ovarian function following M-cell transplantation was also studied. The researchers collected ovaries from two control and three treated monkeys and measured their gene expression. They also employed a wide array of experimental tools, including cell culture-based assays, and gene inactivation experiments that allowed them to find the molecular processes that play a role in the impact of M cells on ovarian aging.

Their results suggest that M-cell therapy led to a decrease in inflammation, fibrosis, oxidative damage, and apoptosis. It also promoted follicle development by increasing cell proliferation, angiogenesis, and hormone response levels in perimenopausal ovaries.

The researchers concluded that their results show the feasibility of using M-cell transplantation to alleviate ovarian aging and the possibility of extending reproductive lifespan, but more research is necessary to establish safety and efficacy in humans.

Yes I will donate❤️

Literature

[1] Yan, L., Tu, W., Zhao, X., Wan, H., Wu, J., Zhao, Y., Wu, J., Sun, Y., Zhu, L., Qin, Y., Hu, L., Yang, H., Ke, Q., Zhang, W., Luo, W., Xiao, Z., Chen, X., Wu, Q., He, B., Teng, M., … Wang, H. (2024). Stem cell transplantation extends the reproductive life span of naturally aging cynomolgus monkeys. Cell discovery, 10(1), 111.

[2] Lobo, R. A., & Gompel, A. (2022). Management of menopause: a view towards prevention. The lancet. Diabetes & endocrinology, 10(6), 457–470.

[3] Nakamura, T., Imai, Y., Matsumoto, T., Sato, S., Takeuchi, K., Igarashi, K., Harada, Y., Azuma, Y., Krust, A., Yamamoto, Y., Nishina, H., Takeda, S., Takayanagi, H., Metzger, D., Kanno, J., Takaoka, K., Martin, T. J., Chambon, P., & Kato, S. (2007). Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell, 130(5), 811–823.

[4] Zhu, D., Chung, H. F., Dobson, A. J., Pandeya, N., Giles, G. G., Bruinsma, F., Brunner, E. J., Kuh, D., Hardy, R., Avis, N. E., Gold, E. B., Derby, C. A., Matthews, K. A., Cade, J. E., Greenwood, D. C., Demakakos, P., Brown, D. E., Sievert, L. L., Anderson, D., Hayashi, K., … Mishra, G. D. (2019). Age at natural menopause and risk of incident cardiovascular disease: a pooled analysis of individual patient data. The Lancet. Public health, 4(11), e553–e564.

[5] Xiong, J., Kang, S. S., Wang, Z., Liu, X., Kuo, T. C., Korkmaz, F., Padilla, A., Miyashita, S., Chan, P., Zhang, Z., Katsel, P., Burgess, J., Gumerova, A., Ievleva, K., Sant, D., Yu, S. P., Muradova, V., Frolinger, T., Lizneva, D., Iqbal, J., … Ye, K. (2022). FSH blockade improves cognition in mice with Alzheimer’s disease. Nature, 603(7901), 470–476.

[6] Zhao, Y., Ma, J., Yi, P., Wu, J., Zhao, F., Tu, W., Liu, W., Li, T., Deng, Y., Hao, J., Wang, H., & Yan, L. (2020). Human umbilical cord mesenchymal stem cells restore the ovarian metabolome and rescue premature ovarian insufficiency in mice. Stem cell research & therapy, 11(1), 466.

[7] Yan, L., Wu, Y., Li, L., Wu, J., Zhao, F., Gao, Z., Liu, W., Li, T., Fan, Y., Hao, J., Liu, J., & Wang, H. (2020). Clinical analysis of human umbilical cord mesenchymal stem cell allotransplantation in patients with premature ovarian insufficiency. Cell proliferation, 53(12), e12938.

[8] Umer, A., Khan, N., Greene, D. L., Habiba, U. E., Shamim, S., & Khayam, A. U. (2023). The Therapeutic Potential of Human Umbilical Cord Derived Mesenchymal Stem Cells for the Treatment of Premature Ovarian Failure. Stem cell reviews and reports, 19(3), 651–666.

[9] Tian, C., He, J., An, Y., Yang, Z., Yan, D., Pan, H., Lv, G., Li, Y., Wang, Y., Yang, Y., Zhu, G., He, Z., Zhu, X., & Pan, X. (2021). Bone marrow mesenchymal stem cells derived from juvenile macaques reversed ovarian ageing in elderly macaques. Stem cell research & therapy, 12(1), 460.

[10] Wu, J., Song, D., Li, Z., Guo, B., Xiao, Y., Liu, W., Liang, L., Feng, C., Gao, T., Chen, Y., Li, Y., Wang, Z., Wen, J., Yang, S., Liu, P., Wang, L., Wang, Y., Peng, L., Stacey, G. N., Hu, Z., … Hao, J. (2020). Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis. Cell research, 30(9), 794–809.

Date Posted: December 10, 2024

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Senescent Cells Protect the Bladder

In Aging Cell, a research team has explained why barrier cells in the human bladder are largely senescent and what might lead them to become cancerous.

Targeting the right cells

It is well-known that people develop urinary problems with advanced age, including increasing frequency and incontinence [1]. However, previous efforts to treat this problem have largely focused on signaling pathways in the smooth muscle in the region rather than the bladder itself, and this has proven to be largely ineffective, with patients often discontinuing prescribed medication [2].

The researchers of this paper note that bladder control is a multifaceted issue, with the brain playing a role [3] along with a decrease in feeling in the area [4] and an increase in fibrosis [5]. This led the researchers to attempt a geroscience-related approach, determining if attempting to treat aging in a broader way might alleviate the issue, focusing specifically on senescent cells in the bladder as a potential therapeutic target to be treated with senolytics.

What they found, however, defied their expectations.

Where senescent cells are necessary

These researchers began their study by determining how senescent cells in the bladders of mice are affected by aging over their lifespans. Interestingly, the researchers only found that, in this area, old female mice had increases in the inflammatory molecules secreted by senescent cells; male mice did not have a statistically significant change.

While the researchers looked at individual molecules in order to establish a pattern, this line of exploration was largely inconclusive, with expected correlations not being established. They used the well-established senescence-associated biomarker SA-β-gal to find these cells, discovering that the only appreciable population was in the surface umbrella cells (UCs), barrier cells that prevent leakage between the bladder and the surrounding tissue.

Unlike most other cells, UCs are normally polyploid: they have multiple copies of chromosomes [6]. These senescent cells were found even in two-month mice, and they increased as the mice matured but did not increase into older ages. Other biomarkers, such as telomere-associated foci (TAF) and γH2AX, which represents damaged DNA, were highly represented in the UC population.

However, there were some crucial differences with aging. The senescent cell marker p16 was not found in this tissue area in middle-aged mice but was found in 10% of the relevant cells of older mice. Genes that prevent death by apoptosis that were expressed in middle-aged mice were less expressed in older mice, while the bladder cells of older mice seemed to be undergoing much more stress.

Being polyploid is likely to mean that UCs are more resistant to stresses and more able to respond to challenges [7], and one paper demonstrated that this is what makes it possible to fulfill their function [8]. However, as polyploidy also makes it much more likely that cells will have problems with missing or extra chromosomes (aneuploidy), there are evolved safeguards against their proliferation, and so previous work has also found that polyploidy is a cause of senescence [9]. These researchers were able to confirm that work, finding that the relevant cell cycle regulator was significantly upregulated in UCs.

Well-known senolytics are ineffective here, and it’s good that they are

While removing senescent cells in this case would not be likely to be beneficial, the researchers tested the well-known combination of dasatinib and quercetin in older mice. The mice’s UC cells were completely unaffected by this treatment: there were no differences in senescent cell population, TAF, nor p16. While there were some changes in gene expression in the whole bladder, the treatment did not offer any appreciable benefits.

Feeding the mice a high-fat diet, which increases systemic inflammation and senescent cell burden, had a small effect on maximum bladder pressure but did not affect other markers, such as the amount voided into corners: while such a diet clearly has some negative effects, it does not recapitulate natural aging. Here, too, senolytics were not found to have any effect.

Injecting the mice with senescent cells had similar effects on maximum pressure. Interesting, injecting mice with proliferating ear fibroblasts seemed to cause the mice to void more in corners.

The researchers note that these senescent cells are clearly necessary for proper function of the bladder, suggesting that they should be treated rather than destroyed, such as by improving their mitochondrial function or reducing their oxidative stress. They also believe that the polyploidy of these cells may be responsible for bladder cancer, as the cell cycle regulator that keeps them senescent is not perfect, and polyploid cells are much more prone to becoming cancerous. The researchers point to this as being part of antagonistic pleiotropy: a benefit earlier in life becomes a danger later on. Time will tell whether this knowledge can be used to develop treatments for bladder problems, including cancer.

Yes I will donate❤️

Literature

[1] Nordling, J. (2002). The aging bladder—a significant but underestimated role in the development of lower urinary tract symptoms. Experimental gerontology, 37(8-9), 991-999.

[2] Benner, J. S., Nichol, M. B., Rovner, E. S., Jumadilova, Z., Alvir, J., Hussein, M., … & Brubaker, L. (2010). Patient‐reported reasons for discontinuing overactive bladder medication. BJU international, 105(9), 1276-1282.

[3] Zhao, P., Zhang, G., Shen, Y., Wang, Y., Shi, L., Wang, Z., … & Sun, L. (2023). Urinary dysfunction in patients with vascular cognitive impairment. Frontiers in Aging Neuroscience, 14, 1017449.

[4] Pfisterer, M. H. D., Griffiths, D. J., Schaefer, PhD, W., & Resnick, N. M. (2006). The effect of age on lower urinary tract function: a study in women. Journal of the American Geriatrics Society, 54(3), 405-412.

[5] Kullmann, F. A., Birder, L. A., & Andersson, K. E. (2015). Translational research and functional changes in voiding function in older adults. Clinics in geriatric medicine, 31(4), 535.

[6] Wang, J., Batourina, E., Schneider, K., Souza, S., Swayne, T., Liu, C., … & Mendelsohn, C. L. (2018). Polyploid superficial cells that maintain the urothelial barrier are produced via incomplete cytokinesis and endoreplication. Cell reports, 25(2), 464-477.

[7] Bailey, E. C., Kobielski, S., Park, J., & Losick, V. P. (2021). Polyploidy in tissue repair and regeneration. Cold Spring Harbor Perspectives in Biology, 13(10), a040881.

[8] Wang, J., Batourina, E., Schneider, K., Souza, S., Swayne, T., Liu, C., … & Mendelsohn, C. L. (2018). Polyploid superficial cells that maintain the urothelial barrier are produced via incomplete cytokinesis and endoreplication. Cell reports, 25(2), 464-477.

[9] Panopoulos, A., Pacios-Bras, C., Choi, J., Yenjerla, M., Sussman, M. A., Fotedar, R., & Margolis, R. L. (2014). Failure of cell cleavage induces senescence in tetraploid primary cells. Molecular biology of the cell, 25(20), 3105-3118.

Date Posted: December 10, 2024

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Longevity Hackers: A Documentary Debuts on How to Stop Aging

Longevity Hackers, an in-depth look at how to slow the human pace of aging, debuts on Apple TV and Amazon beginning December 4, 2024. Produced by Ruben Figueres, directed by Michal Siewierski, and narrated by Academy Award nominee, Edward Norton, the film revolutionizes outdated cultural conceptions and beliefs about aging and offers a behind-the-scenes look at the breakthrough science and biohacking secrets that are adding not just years but healthy, fulfilled years to our lifespan.

“This is probably the most important topic of our generation,” says featured voice Steve Aoki.

Historically, the pairing of aging and disease has been regarded as an inevitability. Today, as the American life expectancy wanes, we enter a new era. Major advancements in longevity research and technology have enabled humans to significantly slow the biological pace of aging by addressing its root causes. By solving for the degenerative changes that come with aging, and removing them from the aging process, most diseases would be eliminated.

Michal Siewierski cites Artificial Intelligence as a major factor: “The irruption of AI technology in the medical field will increase exponentially the speed of the advances. Things that seemed like science fiction a few years ago, are becoming a reality now.”

Hear from Tony Robbins, Mark Cuban, Steve Aoki, Peter Diamandis, Dr. Morgan Levine, Tony Hawk, Chris Bumstead, John Salley, Wim Hof, Chris Mirabile, and other notable voices in the longevity and biohacking community as they share powerful insights and personal regimens to optimize health and add years to your life.

The global longevity market is estimated to reach $610B by 2025 and investment in personal health and wellness remains a top priority. Longevity Hackers demystifies the root causes of aging across exercise, nutrition, recovery, stress management, mental health, and more. Viewers learn about the relationship between sleep and metabolic systems, the dramatic impact joy and purpose in life have on health, and how to track your longevity via biological age testing.

“Biological age is becoming the premier biomarker of our health,” said Chris Mirabile, biohacker and biotech CEO of NOVOS. “The best way to keep track of your lifestyle being conducive to longevity is with a biological age clock, specifically one that’s been proven to be both accurate and precise.”

Aging will look starkly different for current and future generations. Science has shown that only 10% to 20% of lifespan is based on genetics, while lifestyle choices determine the rest. This film will empower humans to take their lives into their own hands by equipping them with the knowledge to do so.

“No matter where you are from, or what your beliefs are, we can all agree that life is a gift that should be cherished,” said Edward Norton. “The people working in the longevity and life extension fields want to extend that gift to humanity.”

‘The Longevity space is growing rapidly. Aging affects every person, regardless of race, religion, political orientation, or any other factors. The fight against aging is something that could unite humanity for a common goal,” said producer Ruben Figueres.

Yes I will donate❤️

Date Posted: December 9, 2024

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Announcing Vitalist Bay, a Pop-Up City in the Bay Area

A unique project is set to go live next spring in the Bay Area. Organized by the Vitalism Foundation, it promises to be one of the largest longevity-related events ever.

They’re popping up!

Since the pop-up city of Zuzalu took the longevity community by storm in early 2023, its innovative concept has inspired a wave of adaptations around the globe. These include Vitalia on the island of Roatan, Honduras; ZuVillage in Georgia (the country, not the state); and Zelar City in Berlin, each offering its own spin on the original formula.

A pop-up city gathers like-minded people, blending co-living with a packed schedule of activities such as conferences, workshops, and hackathons. When the project is longevity-focused, the daily routine revolves around health and wellness, including healthy meals, cold plunges, yoga classes, detailed blood tests, and on-site treatments.

Pop-up cities give participants an inspiring glimpse into a future where people aren’t bound by national borders but instead unite around shared values and interests. This ambitious concept, known as “network states,” was coined by entrepreneur Balaji Srinivasan. Some projects, like Vitalia, have already taken the next step by establishing a continuous presence with a small, permanent community rather than disbanding after a few months.

Betting big on the Bay Area

Most pop-up cities have been set in remote or underdeveloped locations, due to factors like lower costs and relaxed regulations. Building such a project in a bustling, expensive metropolis is a serious challenge – one that Vitalist Bay is stepping up to meet.

Vitalist Bay, a future pop-up city set to operate in Berkeley, California, during April and May of 2025, is being organized by the Vitalism Foundation, a major non-profit in the longevity space. In a press release, the organizers described the initiative as “humanity’s boldest effort to extend healthy lifespan and solve aging” and “the Bay Area’s first longevity zone.”

Like a proper longevity-oriented pop-up city should, Vitalist Bay will offer its inhabitants and visitors perks like a gym, a sauna, a large co-working space, advanced diagnostics such as DEXA scans and VO2max tests, and, generally, a “pro-health social environment.” ‘Bayers’ will also be able to participate in a community clinical trial.

The program

Vitalist Bay boasts an exceptionally comprehensive program covering a variety of interconnected topics, including longevity science, decentralized science and network states, biostasis and cryopreservation, AI in biology, and investment in longevity biotech. Notably, an entire week will focus on healthcare policy, philosophy, and ethics – an encouraging sign of growing interest in longevity advocacy, a vital part of the movement.

“Aging and longevity have such wide scope – from policy and regulations to science and technology, investing in startups, and even crypto with decentralized science. Unfortunately, the interaction between these different areas has been quite limited,” Adam Gries, Vitalism’s co-founder, said to lifespan.io. “Vitalist Bay is longevity’s new capital, which is a triple entendre – human capital, financial capital, and physical capital – because we feel longevity has been missing a focal point that converges its different aspects.”

The locals and the visitors

Despite the Bay Area’s notoriously high cost of living, Vitalist Bay will offer reasonably priced accommodations for several dozen permanent residents. “The event will be centered around the Lighthaven campus, where the rationalist community is based,” said Nathan Cheng, co-founder of Vitalism and the Longevity Biotech Fellowship. “We’ll bring in hundreds, if not thousands, of longevity experts across different domains with the common focus of solving the problem of aging.”

The primary emphasis, however, will be on visitors. “Vitalia and Zuzalu were designed as pop-up cities with residents as the dominant group,” Adam noted. “Our longevity zone is different – the dominant group will be visitors coming for shorter periods. With a venue that can host a thousand people but only 70 residents, we’re expecting thousands of attendees to participate in our conferences.”

Elaborating on why Vitalist Bay differs from its predecessors, Adam added, “Being in the Bay Area is crucial. Long-term pop-up cities in remote locations with limited infrastructure, research ecosystems, or innovation history are inherently restrictive. Think about the 10,000 or more angel investors in the Bay Area; how many would travel to Vitalia? Maybe the hardcore enthusiasts, but not those who are merely curious or geographically tied. With a local event, we can spark engagement beyond the dedicated longevity community.”

What’s next?

“Among the outputs we’re aiming for,” Nathan said, “are policy and ethics statements from philosopher groups, think tanks with recommendations for research funding priorities, and local community partnerships that emphasize the pro-social aspects of longevity. We also want to engage with the local art scene and, more broadly, build projects that bridge different parts of the longevity ecosystem. Of course, we’ll try to get more capital into companies and initiatives, both for-profit and nonprofit.”

Another ambitious goal is to create a longer-term physical presence in the Bay Area. “For that,” Nathan explained, “we’re partnering with Berlin House, which owns a 16-story tower in San Francisco. We’ll be governing one floor dedicated to longevity in partnership with VitaDAO and Foresight Institute. This could become our longer-term venue after the two-month event.”

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Date Posted: December 7, 2024

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BioAge Labs Ends STRIDES Phase 2 Clinical Trial

RICHMOND, Calif., Dec. 06, 2024 (GLOBE NEWSWIRE) — BioAge Labs (Nasdaq: BIOA) (“BioAge”, “the Company”), a clinical-stage biopharmaceutical company developing therapeutic product candidates for metabolic diseases by targeting the biology of human aging, today announced that the Company has made the decision to discontinue the ongoing STRIDES Phase 2 study of its investigational drug candidate azelaprag as monotherapy and in combination with tirzepatide after liver transaminitis without clinically significant symptoms was observed in some subjects receiving azelaprag. No transaminase elevations were observed in the tirzepatide only treatment group.

“Patient safety is our top priority in the conduct of our clinical studies,” said Kristen Fortney, PhD, CEO and co-founder of BioAge. “We made the difficult decision to discontinue the STRIDES Phase 2 study of azelaprag because it became clear that the emerging safety profile of the current doses tested is not consistent with our goal of a best-in-class oral obesity therapy. While this outcome is a significant disappointment, we remain encouraged by azelaprag’s promising preclinical and Ph1b efficacy profile. We remain committed to our focus on developing therapies for metabolic aging. In parallel to assessing the next steps for the azelaprag program, we will continue to advance our NLRP3 inhibitor program as well as additional research programs with novel mechanisms emerging from our platform.”

STRIDES is a randomized, double-blind, placebo-controlled Phase 2 clinical trial of azelaprag as monotherapy and in combination with tirzepatide that planned to enroll approximately 220 individuals with obesity aged 55 years and older (link). The trial was designed to evaluate the efficacy as measured by body weight reduction and other outcomes, safety, and tolerability of two oral doses of azelaprag (300 mg, once or twice daily) in combination with tirzepatide (5 mg subcutaneous injection once weekly). An azelaprag monotherapy arm was included to provide additional safety information.

Of 204 subjects enrolled in STRIDES as of today, 11 subjects in the azelaprag treatment groups were observed to have transaminase elevations with no clinically significant symptoms. Dosing of all subjects will be discontinued, and no additional subjects will be enrolled. Clinical follow-up of enrolled subjects will continue off drug. The Company intends to further analyze available STRIDES clinical data from all enrolled subjects. The Company has notified all study investigators and regulatory authorities including the U.S. Food and Drug Administration (FDA) of the Company’s decision to discontinue enrollment. The Company intends to share updated plans for azelaprag in Q1 2025.

BioAge continues to advance its pipeline of therapeutic candidates targeting the biology of aging to treat metabolic diseases. The Company’s novel class of brain-penetrant NLRP3 inhibitors, which have demonstrated high potency and a novel binding site, are progressing toward IND submission, anticipated in the second half of 2025. The NLRP3 inhibitor program targets neuroinflammation, which is linked to both metabolic and neurodegenerative diseases. In addition, BioAge is advancing multiple targets derived from its proprietary discovery platform, which analyzes molecular data spanning over 50 years of human aging trajectories.

About BioAge Labs, Inc. BioAge is a clinical-stage biopharmaceutical company developing therapeutic product candidates for metabolic diseases, such as obesity, by targeting the biology of human aging. BioAge’s lead product candidate, azelaprag, is an orally available small molecule agonist of APJ that was observed to promote metabolism and prevent muscle atrophy on bed rest in a Phase 1b clinical trial. BioAge is also developing orally available small molecule brain penetrant NLRP3 inhibitors for the treatment of diseases driven by neuroinflammation. BioAge’s preclinical programs, based on novel insights from the company’s discovery platform built on human longevity data, address key pathways in metabolic aging.

Forward-looking statements This press release contains “forward-looking statements” within the meaning of, and made pursuant to the safe harbor provisions of, the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, but not limited to, statements regarding our plans to develop and commercialize our product candidates, our business strategy, results of our ongoing or planned clinical trials, the timing of any future updates to our programs and the clinical utility of our product candidates. These forward-looking statements may be accompanied by such words as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “might,” “plan,” “potential,” “possible,” “will,” “would,” and other words and terms of similar meaning. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: our ability to develop, obtain regulatory approval for and commercialize our product candidates; the timing and results of preclinical studies and clinical trials; the risk that positive results in a preclinical study or clinical trial may not be replicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; risks associated with clinical trials, including our ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates; the occurrence of adverse safety events; failure to protect and enforce our intellectual property, and other proprietary rights; failure to successfully execute or realize the anticipated benefits of our strategic and growth initiatives; risks relating to technology failures or breaches; our dependence on collaborators and other third parties for the development of product candidates and other aspects of our business, which are outside of our full control; risks associated with current and potential delays, work stoppages, or supply chain disruptions; risks associated with current and potential future healthcare reforms; risks relating to attracting and retaining key personnel; failure to comply with legal and regulatory requirements; risks relating to access to capital and credit markets; and the other risks and uncertainties that are detailed under the heading “Risk Factors” included in BioAge’s Form 10-Q filed with the U.S. Securities and Exchange Commission (SEC) on November 7, 2024, and other filings with the SEC filed from time to time. BioAge undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

Contacts PR: Chris Patil, media@bioagelabs.com IR: Elena Liapounova, ir@bioagelabs.com Partnering: partnering@bioagelabs.com Web: https://bioagelabs.com

Date Posted: December 6, 2024

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Nuclear Expression of a Mitochondrial Gene in Mice

Scientists from the Longevity Research Institute (LRI), which was formed by the merger of SENS Research Foundation and lifespan.io, have achieved expression of an essential mitochondrial gene in the nucleus and proper functioning of the protein. This could pave the way for curing diseases caused by mitochondrial mutations [1].

The fragile mitochondrial DNA

The prevailing scientific consensus is that mitochondria were once independent microorganisms that entered a symbiotic relationship with larger cells. This duo gave rise to eukaryotic cells: the building blocks of all multicellular life. Without that fateful “marriage,” complex life would not exist, as mitochondria provide cells with essential energy via oxidative phosphorylation.

Over the millennia, mitochondria have retained their own DNA. However, this mitochondrial DNA (mtDNA) has several vulnerabilities: it lacks the protective proteins that nuclear DNA is wrapped around (histones), has fewer repair mechanisms compared to nuclear DNA, and exists in a harsh environment of oxidative stress generated by its own metabolic activity.

The fragility of mtDNA might have contributed to the relocation of most of its genes to nuclear DNA. Proteins encoded by those genes are synthesized in the cytosol and transported across the cell into mitochondria via a highly regulated process. However, 13 essential proteins involved in oxidative phosphorylation remain encoded by mtDNA and still suffer from the same vulnerabilities. This makes mtDNA prone to mutations, particularly as we age.

Mutations in mtDNA contribute to a range of diseases, such as Leber hereditary optic neuropathy (LHON), and are linked to a wide range of age-related pathologies, including sarcopenia and Alzheimer’s disease [2]. Addressing problems caused by mtDNA mutations is a major challenge in biomedical research. However, in this study, LRI researchers have achieved a significant breakthrough by successfully relocating a mitochondrial gene to the nucleus in vivo.

Overcoming the challenges

Previously, the same team had achieved promising results in vitro [3], but finding a suitable animal model proved difficult: mtDNA genes are so essential that mutations in them usually render mice non-viable. However, a particular strand of mice exists that harbors a relatively benign mutation in ATP8, a gene encoding a subunit of the ATP synthase complex, which causes only a mildly pathologic phenotype. Alongside those mutants, wild-type mice were used as controls.

The team synthesized a nuclear-compatible version of ATP8 and inserted it into the ROSA26 locus, a well-characterized “safe harbor” site in the mouse genome. This locus is widely used in genetic engineering because it allows stable organism-wide expression of inserted genes without interfering with other essential genomic functions.

The researchers had to overcome significant technical challenges to achieve nuclear expression of a gene that is normally expressed in mitochondria (allotopic expression) and to make the protein transferrable to mitochondria. For instance, they found that efficient allotopic expression requires codon optimization: altering the DNA sequence of a gene using codons that are more efficiently translated by ribosomes.

Efficient, persistent, non-immunogenic

Eventually, their efforts paid off: allotopic ATP8 was able to compete with mitochondrial ATP8 even in wild-type mice and outperformed the mutant ATP8. The allotopic gene was expressed in all the tissues that the researchers tested, and the protein successfully integrated into the mitochondrial machinery.

“The key question was ‘How well can an allotopic protein compete with pre-existing protein?’” said Dr. Amutha Boominathan, Assistant Professor and Principal Investigator at LRI and the study’s leading author. “One fundamental concept in the field is that mitochondrial DNA exists because proteins need to be synthesized on demand for easier incorporation into their respective complexes.”

“For allotopic expression to succeed,” she explained, “you must demonstrate that protein coming from the nuclear side can be incorporated with similar efficiency. In wild-type mice, we see equal efficiency between endogenous and exogenous proteins. In our mutant model, we see increasing incorporation over time, suggesting the nuclear protein actually outcompetes the mutated one from a stability perspective.”

Importantly, the allotopic gene functioned well in the genetically modified mice’s offspring for at least four generations, with no adverse effects on fertility. While mtDNA can sometimes trigger an immune reaction when released into the cytoplasm, this gene was also well-tolerated by the immune system, as confirmed by cytokine array analysis.

A blueprint for the future

In the paper, the researchers note that their successful proof of concept does not necessarily apply to all mtDNA genes, and many challenges lie ahead. However, Boominathan is optimistic: “This provides a platform for testing other genes. With appropriate engineering we can overcome all the challenges. We’ve proven it for one protein and have promising data for others. What we’ve demonstrated here is the feasibility of expressing mitochondrial genes in a whole-body context. The inheritance patterns and lack of immune response are particularly encouraging for therapeutic applications.”

There are over 250 mitochondrial DNA diseases that could potentially benefit from this approach, according to Boominathan. “If we can achieve allotopic expression for all 13 genes,” she said, “we’d have a pathway to treat many of these rare diseases.”

The aging connection

LHON, one of the diseases that the researchers are after, “is actually an aging disorder,” Boominathan explained. “While the mutation is inherited, it specifically affects males over 40. These mutations amplify with age, particularly in tissues with high oxidative phosphorylation demands, like retinal ganglion cells. Symptoms only appear when the mutation load reaches a certain threshold.”

This is particularly relevant to post-mitotic cells that form the brain, skeletal muscle, and cardiac tissue since those cells cannot dilute mutations through cell division. “While internal recycling mechanisms like mitophagy exist, they decline with age,” said Boominathan. “If you inherit a mutation or acquire one early in life, it amplifies over time as mitophagy decreases, and these mutations often have an advantage that helps them take over.”

A three-pronged approach

“This work represents the culmination of more than a decade’s worth of effort to provide a genetic backup system for mitochondrial DNA in mammals, for which inherited mutations cause disease in nearly 1 in 200 people,” said Dr. E. Lillian Fishman, Director of Research and Education at LRI, about the study. “I am proud of Dr. Boominathan and her team’s persistence to rise to meet this technically challenging proof-of-concept that paves the way for the treatment of debilitating mitochondrial diseases like Leigh’s syndrome and progressive diseases of aging.”

This study was done as part of MitoSENS, a wider LRI project that includes a three-pronged approach to mitochondrial dysfunction. In addition to allotopic mtDNA expression, the researchers pursue boosting mitophagy with small molecules and de novo synthesis of healthy mtDNA for transfer into exogenous mitochondria, followed by introduction into cells.

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Literature

[1] Begelman, D. V., Dixit, B., Truong, C., King, C. D., Watson, M. A., Schilling, B., … & Boominathan, A. (2024). Exogenous Expression of ATP8, a Mitochondrial Encoded Protein, From the Nucleus In Vivo. Molecular Therapy Methods & Clinical Development.

[2] Zhunina, O. A., Yabbarov, N. G., Grechko, A. V., Yet, S. F., Sobenin, I. A., & Orekhov, A. N. (2020). Neurodegenerative diseases associated with mitochondrial DNA mutations. Current Pharmaceutical Design, 26(1), 103-109.

[3] Boominathan, A., Vanhoozer, S., Basisty, N., Powers, K., Crampton, A. L., Wang, X., … & O’Connor, M. S. (2016). Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant. Nucleic acids research, 44(19), 9342-9357.

Date Posted: December 5, 2024

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Fragmented Mitochondria Linked to Muscle Weakness

In a study published in Aging Cell, researchers have outlined a relationship between mitochondrial fragmentation in skeletal muscle and the loss of strength with age.

Broken power plants

Mitochondrial Dysfunction

As they age, the mitochondria in our cells lose their ability to provide cellular energy and release reactive oxygen species that harm cells and cause increasing levels of systemic inflammation.
Read More

As its authors point out, this is far from the first study to link mitochondrial dysfunction and aging in muscle [1], nor is it the first to connect exercise habits, aging, mitochondria, and the loss of physical function [2].

There has also been significant prior work showing how the mitochondria in muscle tissue behave. Mitochondria in muscle are not equal in their behaviors: the mitochondria closest to the blood-filled capillaries (subsarcolemmal mitochondria) bring energy to more centrally located ones (intermyofibrillar mitochondria) through an intracellular network [3]. Fragmentation of this network destroys this energy transfer but may also offer protection against damage being transferred as well [4].

Too much fragmentation and fission, however, causes muscle wasting in mice [5]; the opposite, mitochondrial fusion, causes muscles to grow in these animals [6]. The researchers’ previous work on healthy volunteers demonstrated that fragmentation begins to occur at day 6 of bed rest, while functional impairments were found to occur on day 55 [7]. However, that work did not prove one way or another whether mitochondrial fragmentation is a useful biomarker or warning sign for age-related muscle decline.

Decline begins before retirement

Wanting to avoid physical inactivity as a confounder and suspecting that this process may not be the same as actual sarcopenia, the researchers recruited a dozen young (average age 27) and ten middle-aged (average age 55) volunteers rather than significantly older people. The older group was slightly more overweight than the younger group.

Unsurprisingly, the younger people’s muscles used more oxygen to generate more power than the older people’s, according to multiple metrics of respiration and energy use. This was not linked to blood flow; instead, it was linked to how the muscles pull oxygen from the blood.

The researchers then examined the mitochondria more closely in biopsied muscle tissue. The total density of the intermyofibrillar mitochondria was the same between younger and older people; however, the older people had more, smaller mitochondria. While their shapes did not differ, markers of mitochondrial fragmentation were greater in this area in the older group.

In the subsarcolemmal area, however, the older people had approximately as many mitochondria as the younger people, which led to a reduction of density with age as these mitochondria were also smaller. Here, too, they were found to be significantly more fragmented. This fragmentation in both areas was associated with the accumulation of fat (lipid) droplets.

Looking ever closer

There were also differences involving the tiny folds inside mitochondria (cristae). Younger people’s mitochondria had regular and dense cristae, while those of older people were less regular, with some areas having no cristae at all. This, the researchers hold, represents “age-associated deterioration at the level of the individual mitochondrion.” Interestingly, however, further data suggests that the increased number of smaller mitochondria may have made up for this, restoring some of the lost function.

The authors then pivoted to the key thrust of their research: the connection between fragmentation and loss of capacity. Fragmentation in the intermyofibrillar mitochondria and a reduction in the cristae was found to be responsible for nearly all of the changes in the well-known metric of VO2max. Unsurprisingly, the density of the subsarcolemmal mitochondria was found to be associated with the muscles’ ability to extract oxygen from blood.

The researchers believe that their findings explain the basic reasons why people lose strength with age, even in the absence of defined sarcopenia. They also warn that this mitochondrial dysfunction only gets worse with aging. Furthermore, they hold that their findings “reflect an early ageing phenotype, making the mitochondrial changes observed herein strong candidates for intervention studies aiming to slow the progression of the effects of ageing on physical function.”

As exercise is associated with mitochondrial fusion [8] and one study had suggested that six months of endurance training can compensate for 30 years of aging [9], the authors suggest that further research on exercise in older people should be done with a close examination into mitochondrial changes.

Yes I will donate❤️

Literature

[1] Gouspillou, G., Bourdel‐Marchasson, I., Rouland, R., Calmettes, G., Biran, M., Deschodt‐Arsac, V., … & Diolez, P. (2014). Mitochondrial energetics is impaired in vivo in aged skeletal muscle. Aging cell, 13(1), 39-48.

[2] Grevendonk, L., Connell, N. J., McCrum, C., Fealy, C. E., Bilet, L., Bruls, Y. M., … & Hoeks, J. (2021). Impact of aging and exercise on skeletal muscle mitochondrial capacity, energy metabolism, and physical function. Nature communications, 12(1), 4773.

[3] Glancy, B., Hartnell, L. M., Malide, D., Yu, Z. X., Combs, C. A., Connelly, P. S., … & Balaban, R. S. (2015). Mitochondrial reticulum for cellular energy distribution in muscle. Nature, 523(7562), 617-620.

[4] Glancy, B., Hartnell, L. M., Combs, C. A., Femnou, A., Sun, J., Murphy, E., … & Balaban, R. S. (2017). Power grid protection of the muscle mitochondrial reticulum. Cell reports, 19(3), 487-496.

[5] Romanello, V., Guadagnin, E., Gomes, L., Roder, I., Sandri, C., Petersen, Y., … & Sandri, M. (2010). Mitochondrial fission and remodelling contributes to muscle atrophy. The EMBO journal, 29(10), 1774-1785.

[6] Cefis, M., Dargegen, M., Marcangeli, V., Taherkhani, S., Dulac, M., Leduc‐Gaudet, J. P., … & Gouspillou, G. (2024). MFN2 overexpression in skeletal muscles of young and old mice causes a mild hypertrophy without altering mitochondrial respiration and H2O2 emission. Acta Physiologica, 240(5), e14119.

[7] Eggelbusch, M., Charlton, B. T., Bosutti, A., Ganse, B., Giakoumaki, I., Grootemaat, A. E., … & Wüst, R. C. (2024). The impact of bed rest on human skeletal muscle metabolism. Cell Reports Medicine, 5(1).

[8] Huertas, J. R., Ruiz‐Ojeda, F. J., Plaza‐Díaz, J., Nordsborg, N. B., Martín‐Albo, J., Rueda‐Robles, A., & Casuso, R. A. (2019). Human muscular mitochondrial fusion in athletes during exercise. The FASEB Journal, 33(11), 12087-12098.

[9] McGuire, D. K., Levine, B. D., Williamson, J. W., Snell, P. G., Blomqvist, C. G., Saltin, B., & Mitchell, J. H. (2001). A 30-year follow-up of the Dallas Bed Rest and Training Study: II. Effect of age on cardiovascular adaptation to exercise training. Circulation, 104(12), 1358-1366.

Date Posted: December 5, 2024

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AI Outperforms AI-Assisted Doctors in Diagnostic Reasoning

In a new study, ChatGPT 4.0 achieved significantly better diagnostic scores when evaluating complex cases than either unassisted human physicians or physicians who consulted the chatbot [1].

Bad news for human doctors?

For millions of people, chatbots powered by large language models (LLMs) have quickly become an indispensable source of information on everything from finances to relationships. These digital aids often come across as more knowledgeable, polite, patient, and compassionate than human experts.

It has been questioned, however, if it is really a smart idea to turn to a robot for medical advice. In what could be a troubling sign for general practitioners, chatbots have shown they can outperform humans in this area too. A study from May of last year found that the earlier version of ChatGPT, 3.5, handily outclassed human health professionals in answering patients’ questions. Responses from both the bot and verified physicians were graded by a panel of health experts, and the gap was striking: for instance, 27% of human answers were deemed “unacceptable” compared to just 2.6% of machine-generated ones.

That study had relied on doctor responses pulled from Reddit, but a more recent study went further. Earlier this year, researchers at Google developed a dedicated model called Articulated Medical Intelligence Explorer (AMIE) and tested it against human primary care practitioners. Wide-ranging health scenarios were distributed at random, with actors playing the roles of patients who discussed their cases with either the chatbot or a human physician without knowing who was who. According to expert evaluators, AMIE outperformed its human counterparts in 24 of 26 categories, including empathy.

“Meet my assistant, ChatGPT”

In a new study published in JAMA Network Open, Stanford researchers stripped AI of its perceived edge in empathy and bedside manner. They eliminated the patient interaction element entirely, tasking either ChatGPT 4.0 or 50 human physicians (26 attendings and 24 residents) with diagnosing six carefully selected cases. These cases had never been published before, ensuring that the LLM could not have encountered them during training.

Here’s the twist: half of the doctors were allowed to consult ChatGPT. The aim was to gauge whether physicians would embrace AI as an assistant and whether doing so would improve their diagnostic reasoning. All participants could also use conventional resources like medical manuals.

The primary outcome was a composite diagnostic reasoning score developed by the researchers, which measured accuracy in differential diagnosis, the appropriateness of supporting and opposing factors, and next diagnostic steps. Secondary outcomes included time spent per case and final diagnosis accuracy.

In the end of the day, the LLM dominated yet again, with a median score of 92% per case: 14 points higher than the non-LLM-assisted human group. It also achieved 1.4 times greater accuracy in the final diagnosis. Interestingly, the group of physicians consulting the chatbot didn’t fare much better than their non-assisted peers, scoring 76% versus 74%.

Why didn’t consultation work?

The researchers had anticipated that consulting the LLM would give physicians a marked advantage, but that wasn’t the case. “Our study shows that ChatGPT has potential as a powerful tool in medical diagnostics, so we were surprised to see its availability to physicians did not significantly improve clinical reasoning,” said study co-lead author Ethan Goh, a postdoctoral scholar in Stanford’s School of Medicine and research fellow at Stanford’s Clinical Excellence Research Center.

Why the lackluster collaboration? The authors suggest a few reasons. First, participants weren’t simply asked to provide a diagnosis. Instead, they had to demonstrate diagnostic reasoning by suggesting three possible diagnoses and explaining how they reached their final choice. The chatbot excelled at this aspect, while humans sometimes struggled to articulate their thought processes. This echoes longstanding challenges in modeling human diagnostic reasoning in computer systems before the advent of LLMs.

“What’s likely happening is that once a human feels confident about a diagnosis, they don’t ‘waste time or space’ on explaining their reasoning,” said Jonathan H. Chen, Stanford assistant professor at the School of Medicine and the paper’s senior author. “There’s also a real phenomenon where human experts can’t always articulate exactly why they made the right call.”

Another hurdle was that physicians often dismissed valid suggestions from their AI co-pilot, a sign that overcoming the natural sense of superiority toward machines may take time.

Finally, the researchers noted that the chatbot’s performance hinges on the quality of the prompts it receives. The research team crafted sophisticated prompts to get the most out of ChatGPT, while human participants often used it more like a search engine, asking short, direct questions instead of providing full case details. “The findings suggest there are opportunities for further improvement in physician-AI collaboration in clinical practice and health care more broadly,” Goh said.

One intriguing secondary finding was that doctor-LLM pairs completed cases slightly faster than doctors working solo. While, according to the paper, the difference of slightly more than a minute was negligible, Goh argues that even a small efficiency gains could help make doctors’ lives more efficient. “Those time savings alone could justify the use of large language models and could translate into less burnout for doctors in the long run,” he said. However, more rigorous studies are needed to fully understand this potential benefit.

AI will not replace doctors (until it will)

The authors of studies like this one have been careful to emphasize that AI is not a true substitute for a human health practitioner. “AI is not replacing doctors,” Goh reassures. “Only your doctor will prescribe medications, perform operations, or administer any other interventions.”

Still, it may only be a matter of time before AI demonstrates superiority over human physicians in nearly every aspect of care. Furthermore, vast regions of the world currently face limited access to healthcare, leaving many people without the option of consulting a human doctor at all. In such contexts, AI could fill a critical gap. Just as some countries skipped the landline phase entirely and adopted mobile phones, they might also be the first to transition to predominantly AI-driven healthcare, facing fewer entrenched bureaucratic barriers.

Building on this study, Stanford University, Beth Israel Deaconess Medical Center, the University of Virginia, and the University of Minnesota have joined forces to create AI Research and Science Evaluation (ARiSE), a network dedicated to evaluating generative AI outputs in healthcare.

Yes I will donate❤️

Literature

[1] Goh, E., Gallo, R., Hom, J., Strong, E., Weng, Y., Kerman, H., … & Chen, J. H. (2024). Large language model influence on diagnostic reasoning: a randomized clinical trial. JAMA Network Open, 7(10), e2440969-e2440969.

Date Posted: December 4, 2024

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Can AI Predict Your Death?

Once confined to the realms of science fiction or relatively crude internet death calculators, AI-driven predictions about longevity are inching closer to reality. Questions about the accuracy and value of these forecasts remain.

In recent years, researchers and companies around the globe have been pursuing answers to the ultimate question: How long have we got left? These models leverage cutting-edge tools, such as artificial intelligence and machine learning, drawing on a variety of parameters to deliver statistically grounded insights.

Conceptually, they function like established diagnostic tools such as QRisk for heart disease or CHA₂DS₂-VASc Score for stroke risk. Yet, the debate remains: are these predictions meaningful advancements or little more than modern-day fortune-telling?

The tech behind lifespan prediction

With the advent of artificial intelligence, increasing numbers of tools are emerging on the market. At the same time, biotech companies, such as Altos Labs and BioAge Labs, among others, are engaging such technologies to develop state-of-the-art therapeutics.

AI isn’t a one-stop fix for all challenges. The reality is that it’s a technological tool, albeit with immense potential, that utilizes sophisticated algorithms to get results, much like any other modern technology.

The same approach applies to lifespan prediction technologies built on AI. They engage a suite of technologies, such as:

Neural networks. These mimic the brain’s architecture, similarly to neurons making connections, and help uncover complex patterns in health and lifestyle data.
Machine learning algorithms. These analyze high-dimensional datasets, including genomic sequences, wearable device outputs and lifestyle choices, to establish relationships that could impact aging.
Random forests and decision trees. These can help to identify the critical biomarkers or lifestyle factors that influence the human lifespan.

The power of big data

Perhaps one of the major advantages of AI over traditional solutions hinges on its capabilities in analyzing extensive data sets. These can include:

Lifestyle metrics. By tabulating diet, exercise, sleep patterns, and other defined factors, it becomes possible to establish their roles in both healthspan and lifespan.
Medical history. This data can offer insights into chronic illnesses, prior interventions, and potential risk factors for the future.
Genomic data. Identifying hereditary risk factors and aging-related genes can establish possible risk levels.
Real-time biometrics. Data gathered from wearable technology, such as heart rate and oxygen levels, can provide insights to overall health longitudinally.

By combining these together, a bigger picture can be established that analyzes the probability of a patient developing a disease or condition or experiencing a negative health outcome within a specific period.

The relationship of risk and lifespan

Predicting the risks of specific diseases is not the same as predicting lifespan, and there may be ethical, moral, and legal concerns. To predict lifespan itself, companies working in this sector often choose to focus on specific metrics: biomarkers of aging.

Epigenetic clocks. These are used to evaluate DNA methylation patterns in order to estimate biological age. Tools such as GrimAge and DeepAge are already using this technology.
Blood and wearable biomarkers. These can be used to detect changes in inflammation or metabolism. Tthey offer real-time insights into health trajectories and risk factors.
Lifestyle biomarkers. These integrate diet, stress, and physical activity in order to allow an AI to suggest actionable interventions that could potentially improve lifespan.

Companies exploring lifespan prediction

Despite the challenges, scientific and human curiosity drive companies to seek answers to those all-important questions. Currently, multiple companies are focused on lifespan and on measuring specific risk factors.

Life2vec: This company offers a transformer-based AI model that analyzes life trajectories, predicting events such as death and health outcomes. It draws upon comprehensive datasets from six million individuals to make its predictions. These include socioeconomic, health, and behavioral data for granular predictions. According to the company’s stats, its accuracy rate is between 70% to 90%; however, it remains unclear how this is calculated.

AI-ECG Risk Estimation (Aire): Aire draws upon electrocardiograms (ECGs) to predict mortality risk. It does so by identifying subtle changes in the heart’s function and potential abnormalities. Estimates from the NHS show its accuracy at 78%.

Impacts to accuracy

As this is a new technology, questions arise relating to its accuracy. For example, Life2vec is a transformer-based system that integrates vast datasets to predict mortality risk with a level of granularity. However, challenges remain:

Fundamental limitations. Pinpointing death remains an almost unattainable goal. It’s almost impossible to approximate perfect accuracy even with a personalized risk assessment.
Data bias. AI models are often trained on data sets that lack diversity, which limits their accuracy and can make them biased in certain populations. It’s likely that such models require the same sorts of adjustments as BMI calculators.
Complexity of aging. This is a developing field, and models will struggle to account for all factors and assign the correct weights to them. In addition, evolving factors, such as emerging illnesses, pandemics, and accidents, will always play a role in lifespan.

Ethics

Like the practicalities of proving accuracy and efficacy, utilizing predictive AI technology for human health has a vast range of legal and ethical implications.

Data privacy. Health data is confidential and subject to a variety of laws, depending on jurisdiction. Misuse or incorrect use could lead to situations that result in updates to healthcare laws and data protection legislation.
Ownership and consent. Failure to get informed consent could lead to issues with the ownership of data behind AI predictions. This issue has already arisen with companies such as 23andMe, which have faced criticism for sharing genetic data with third parties.
Bias and inequality. AI is designed by human programmers that might miss biased data in datasets, which could lead to inaccuracies among some populations and possible legal implications.
Psychological impact. Just as knowing a risk factor could have health implications, so too could knowing one’s predicted lifespan. This may cause additional unwanted health outcomes, such as anxiety, depression, and orthorexia.

World Health Organization (WHO) has been vocal about such issues and calls for transparent algorithms and ethical frameworks to govern the use of AI tools in health.

The future of lifespan prediction

Advancements are on the horizon. Moving forward, the next generation of tools for enhanced biomarker analysis could seek to integrate more complex and accurate data from epigenetic clocks, wearable devices, and molecular studies. This would allow them to deliver highly personalized lifespan predictions, even if accuracy remains a point of contention.

In addition to this, wearable technology, such as watches or rings, could enable real-time updates, dynamically adjusting predictions based on daily health behaviors. This could foster a nudge-style approach to health management.

Healthspan prediction has the potential to seamlessly integrate into everyday routines, especially for consumer technology and interactions with medical practitioners. This could enable doctors to tailor healthcare treatments to include preventive care and interventions based on an individual’s projected lifespan and biomarkers.

Of course, there are much broader implications to implementing these technologies in day-to-day life, and they extend beyond healthcare to such things as societal issues, personal finance, and the relationship of work to life, which are also affected by enhanced lifespans.

Do we need to know the future?

AI’s potential to analyze data and predict outcomes is something never seen before. As the world, including healthcare, learns how to adapt to this, this knowledge should always be taken with a pinch of salt. Validating predictive tools to the level where they can be reliably used necessitates rigorous testing for accuracy and consideration of how they should be used.

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The Blog

Building a Future Free of Age-Related Disease

About BioAge Labs, Inc.

Forward-looking statements

Contacts

Exercising your way to longevity

Olympians’ decreased age acceleration

Sex-specific age acceleration patterns

The sport matters

The cellular level

Long-lasting effects

Literature

A well-known laboratory senolytic

Intriguing but positive effects

Is a topical approach best?

Literature

The quest for a true stem cell hair treatment

Hair cells become senescent quickly in culture

A senolytic solution

Literature

Where does XPRIZE Healthspan stand as of now?

Just to clarify: a team will still be able to participate if they submit after December 20th, correct?

So, you are encouraging teams to reach out to you.

How many teams have already applied, and what is their geographic makeup?

What is the distribution in terms of academia versus for-profits?

Do you require teams to be legal entities?

Does the prize structure advantage certain types of teams?

Can you give any advice to the competitors?

Can you expand on your endpoints? Making it about restoring function was an interesting decision.

What you’re saying is that the prize will advance the field regardless of the results, for instance, by improving our understanding of how to measure aging.

A bonus prize is an interesting idea, especially for developing biomarkers of aging, which is a pressing need in our field. This brings me to the question: is the prize open to additional sponsors?

You seem fired up about this project. What does it mean to you personally?

We received some information after this interview was completed:

From crypto to longevity

The philosophy and the team

Leading by example

What is the new fund’s “secret formula” for success?

Many venture funds are cautious about the long-term and uncertain nature of investing in longevity biotech. However, LongGame seems to embrace it, even in its name. Are you really in this for the long haul?

What are your predictions for the near future of longevity biotech, particularly in light of recent setbacks like BioAge discontinuing its Phase II trial? Are we entering “the valley of death”?

How do you intend to measure life extension outcomes (e.g., +10 years, +30 years)?

Increasing healthspan by delaying menopause

Perimenopausal Chinese women’s ovarian reserve

Alleviating ovarian aging with stem cells

Extending reproductive span

Molecular mechanism

Literature

Targeting the right cells

Where senescent cells are necessary

Well-known senolytics are ineffective here, and it’s good that they are

Literature

They’re popping up!

Betting big on the Bay Area

The program

The locals and the visitors

What’s next?

The fragile mitochondrial DNA

Overcoming the challenges

Efficient, persistent, non-immunogenic

A blueprint for the future

The aging connection

A three-pronged approach

Literature

Broken power plants

Decline begins before retirement

Looking ever closer

Literature

Bad news for human doctors?

“Meet my assistant, ChatGPT”

Why didn’t consultation work?

AI will not replace doctors (until it will)

Literature

The tech behind lifespan prediction

The power of big data

The relationship of risk and lifespan

Companies exploring lifespan prediction

Impacts to accuracy

Ethics

The future of lifespan prediction

Do we need to know the future?

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