Mois : décembre 2024

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

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.

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.

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.

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.