Mois : juillet 2024

On July 26, 2024, the 11th Aging Research and Drug Discovery meeting had to stop registrations after reaching full capacity. It sold out two weeks faster than in 2023, a month prior to the start of the conference.

The conference is a non-profit volunteer-run event organized and hosted by the University of Copenhagen. It brings together top academics in aging research, executives and scientists of big pharmaceutical and biotechnology companies, investors, media and startups. In 2024, over 40 startups sponsored the conference demonstrating rapid growth of the Longevity Biotechnology Industry.

11th ARDD will feature the first Healthspan XPrize Summit, the $101 million prize dedicated to teams conducting human healthspan clinical trials to accelerate aging research at scale.

“XPRIZE Healthspan is setting out to revolutionize the way we think about and treat aging through the development of therapeutics that target biological aging rather than disease,” said Jamie Justice, Ph.D., Executive Director of XPRIZE Healthspan, XPRIZE. “In order to accomplish this, we need partners like ARDD to help bring together global thought leaders that can create a future where healthy aging is made possible for everyone.”

“I’m extremely excited about this year’s ARDD. We have a stellar academic lineup and an incredibly strong presence from leading companies in the aging field. This year the presence of pharma companies including Lilly, Lundbeck, Novartis, Regeneron and many others have been strengthened and we are super excited that XPRIZE will host their XPRIZE Healthspan Team Summit at ARDD. We are continuing to offer 3 travel grants for young scholars to attend ARDD and give generous poster awards for the top poster presentations. This edition of ARDD is shaping up to be a fantastic conference. Tickets are limited so we encourage everyone to sign up early to secure a spot in Copenhagen. I very much look forward to seeing old and new friends here in Copenhagen.” said Morten Scheibye-Knudsen, MD, Ph.D., University of Copenhagen.

“I’m genuinely thrilled about the upcoming ARDD conference this year! Building on the incredible success and full bookings of last year’s event, this year promises again unique opportunities to connect with brilliant minds, fostering collaboration and showcasing groundbreaking research. What makes this year even more special is that we are eagerly welcoming even more pharmaceutical companies to join us on this journey. But that’s not all – we’re proud to announce our collaboration with XPRIZE. So, mark your calendar and join us at ARDD2024.” said Daniela Bakula, Ph.D., University of Copenhagen.

“Launched four years ago, Longevity Medicine Day, as an integral part at the ARDD Conference, has rapidly expanded from a workshop to a comprehensive Longevity Medicine Track. This track offers a dynamic forum for physicians, government officials, and key stakeholders to explore the latest advancements and set new standards in the evolving field of longevity medicine.” said Prof. Evelyne Bischof, organizer of ARDD Longevity Medicine Track.

“The ARDD conference was established to bring top academics with the highest-level of credibility together with the biopharmaceutical companies and investors. And for 11 years in a row the conference grew in size and in prominence. And now that big pharma companies realized the value of targeting chronic conditions like obesity and metabolic diseases and are going into muscle wasting and neurology, it became the most premium event in the field. I am happy to see that this year it sold out faster than last year and the number of sponsoring startups has increased. Tier 3 sponsorships sold out faster than registrations and next year, we expect even more startups joining the field”, said Alex Zhavoronkov, Ph.D., founder and CEO of Insilico Medicine.

About Aging Research and Drug Discovery Conference

At ARDD, leaders in the aging, longevity, and drug discovery field will describe the latest progress in the molecular, cellular and organismal basis of aging and the search for interventions. Furthermore, the meeting will include opinion leaders in AI to discuss the latest advances of this technology in the biopharmaceutical sector and how this can be applied to interventions. Notably, this year we will have a special day called Longevity Medicine Day, specifically for physicians where the leading-edge knowledge of clinical interventions for healthy longevity will be described. ARRD intends to bridge clinical, academic and commercial research and foster collaborations that will result in practical solutions to one of humanity’s most challenging problems: aging. Our quest? To extend the healthy lifespan of everyone on the planet.

The authors of a recent review investigated what is known about gut microbiota in centenarians and how gut microbes can help people achieve extreme longevity [1].

What makes centenarians special?

One way of investigating what gives people longevity and health in older ages is to study people who have achieved it, especially those who have lived for a hundred years: centenarians.

It is not yet completely understood how centenarians differ from people who were unable to live so long. Many factors, including lifestyle factors and genetics, can impact whether a person can live to old age in good health, but there is still not enough understanding of what makes centenarians so special.

The authors of this review looked into a potential factor with a tremendous impact on metabolism and health: gut microbiota, the microbes that live in the human gut. They collected scientific evidence regarding these microbioes’ impact “as a potential protective factor for achieving extreme longevity.”

Inflammation and microbiota

Inflammaging, the low-grade chronic inflammation that accompanies aging, and its negative impact on health are widely known. Inflammaging also disrupts gut microbes. This review’s authors explain that such chronic inflammation creates conditions in which certain species of microbes associated with better health have difficulty growing and reproducing. Simultaneously, those conditions are favorable to microbes associated with unhealthy aging, which are known as pathobionts. Therefore, studying centenarians’ microbiota can help to answer questions about how inflammaging-protective mechanisms can develop.

Centenarians’ microbial composition

The composition of microbiota changes with age. Some microbes are lost and replaced by new microbes, which can involve potential pathobionts. This transition is a possible target for interventions.

Research done in the Blue Zones, geographical areas with a high rate of long-lived populations, demonstrated that individuals living there have gut microbiomes enriched in microbes that are considered beneficial and are linked to healthier body mass index, immunomodulation, and homeostasis [2, 3].

The authors also gathered evidence from several studies that looked at how centenarians’ microbiota differ from non-centenarians’. They noted that the microbes that were increased in the centenarians were associated with protection against inflammatory bowel disease, metabolic syndromes, obesity, and diabetes [4] along with prevention of colitis [5], liver disease [6], psychiatric disorders [7], and anxiety and depressive disorders [8]. Additionally, they possess an antitumor effect [9].

On the other hand, microbes whose levels are decreased in the centenarians possess “antioxidant and anti-inflammatory effects,” and decreased levels of one of the groups “is associated with inflammatory bowel diseases, irritable bowel syndrome, obesity, liver disorders, metabolic conditions, cancer, neurological conditions, and dermatitis” [10].

Microbial metabolites and longevity

Changes in microbiota composition are related to changes in metabolites produced by microbes. Those have also been investigated. A study on Italian centenarians revealed changes in the modifications of some lipid groups. Researchers also observed “decreased circulating levels of lipid peroxidation markers,” that is, decreased lipid deterioration by reactive oxygen species [11].

On the other hand, research also identified that some metabolites produced by microbiota can be a marker of shorter life expectancy. For example, evidence from cohorts in the United States shows that the presence of metabolic products of citric acid and bile acid metabolism is associated with a lower likelihood of reaching the age of 80 [12]. However, there is contradictory evidence from cohorts located in Bama, China, which is one of the Blue Zones. Centenarians from that cohort have high fecal short-chain fatty acids and total bile acids [13]. Untangling these seemingly contradictory results would require further investigation.

The need to expand research

The authors point that there is still very limited evidence regarding centenarians’ microbiota, which is not surprising given the diversity of the microorganisms in the human gut, “which can vary based on geographic location, lifestyles, medication, or associated diseases.” Gaining more solid data in this area can lead to the identification of therapeutic targets, allow for designing interventions to change the composition of microbes, or serve as a biomarker.

The authors suggest that future studies should investigate in more depth how microbial composition evolves through life and how it impacts the lifespan of an individual. Based on previous data on this subject, they suggest that such variables as “mode of birth, type, and quality of postnatal breastfeeding, environmental exposure, and hygienic conditions” and their role in the connection between gut microbes, longevity, and healthy aging should be investigated.

Literature

[1] Lozada-Martinez, I. D., Lozada-Martinez, L. M., & Anaya, J. M. (2024). Gut microbiota in centenarians: A potential metabolic and aging regulator in the study of extreme longevity. Aging medicine (Milton (N.S.W)), 7(3), 406–413.

[2] Wang, F., Yu, T., Huang, G., Cai, D., Liang, X., Su, H., Zhu, Z., Li, D., Yang, Y., Shen, P., Mao, R., Yu, L., Zhao, M., & Li, Q. (2015). Gut Microbiota Community and Its Assembly Associated with Age and Diet in Chinese Centenarians. Journal of microbiology and biotechnology, 25(8), 1195–1204.

[3] Kong, F., Hua, Y., Zeng, B., Ning, R., Li, Y., & Zhao, J. (2016). Gut microbiota signatures of longevity. Current biology : CB, 26(18), R832–R833.

[4] Rodrigues, V. F., Elias-Oliveira, J., Pereira, Í. S., Pereira, J. A., Barbosa, S. C., Machado, M. S. G., & Carlos, D. (2022). Akkermansia muciniphila and Gut Immune System: A Good Friendship That Attenuates Inflammatory Bowel Disease, Obesity, and Diabetes. Frontiers in immunology, 13, 934695.

[5] Jia, D. J., Wang, Q. W., Hu, Y. Y., He, J. M., Ge, Q. W., Qi, Y. D., Chen, L. Y., Zhang, Y., Fan, L. N., Lin, Y. F., Sun, Y., Jiang, Y., Wang, L., Fang, Y. F., He, H. Q., Pi, X. E., Liu, W., Chen, S. J., & Wang, L. J. (2022). Lactobacillus johnsonii alleviates colitis by TLR1/2-STAT3 mediated CD206+ macrophagesIL-10 activation. Gut microbes, 14(1), 2145843.

[6] Zhao, Y., Li, C., Luan, Z., Chen, J., Wang, C., Jing, Y., Qi, S., Zhao, Z., Zhang, H., Wu, J., Chen, Y., Li, Z., Zhao, B., Wang, S., Yang, Y., & Sun, G. (2023). Lactobacillus oris improves non-alcoholic fatty liver in mice and inhibits endogenous cholesterol biosynthesis. Scientific reports, 13(1), 12946.

[7] Yun, S., Park, H., Shin, Y., Ma, X., Han, M. J., & Kim, D. (2023). Lactobacillus gasseri NK109 and Its Supplement Alleviate Cognitive Impairment in Mice by Modulating NF-κB Activation, BDNF Expression, and Gut Microbiota Composition. Nutrients, 15(3), 790.

[8] Duranti, S., Ruiz, L., Lugli, G. A., Tames, H., Milani, C., Mancabelli, L., Mancino, W., Longhi, G., Carnevali, L., Sgoifo, A., Margolles, A., Ventura, M., Ruas-Madiedo, P., & Turroni, F. (2020). Bifidobacterium adolescentis as a key member of the human gut microbiota in the production of GABA. Scientific Reports, 10(1).

[9] Wu, L., Xie, X., Li, Y., Liang, T., Zhong, H., Yang, L., Xi, Y., Zhang, J., Ding, Y., & Wu, Q. (2022). Gut microbiota as an antioxidant system in centenarians associated with high antioxidant activities of gut-resident Lactobacillus. NPJ biofilms and microbiomes, 8(1), 102.

[10] Martín, R., Rios-Covian, D., Huillet, E., Auger, S., Khazaal, S., Bermúdez-Humarán, L. G., Sokol, H., Chatel, J. M., & Langella, P. (2023). Faecalibacterium: a bacterial genus with promising human health applications. FEMS microbiology reviews, 47(4), fuad039.

[11] Collino, S., Montoliu, I., Martin, F. P., Scherer, M., Mari, D., Salvioli, S., Bucci, L., Ostan, R., Monti, D., Biagi, E., Brigidi, P., Franceschi, C., & Rezzi, S. (2013). Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism. PloS one, 8(3), e56564.

[12] Montoliu, I., Scherer, M., Beguelin, F., DaSilva, L., Mari, D., Salvioli, S., Martin, F. P., Capri, M., Bucci, L., Ostan, R., Garagnani, P., Monti, D., Biagi, E., Brigidi, P., Kussmann, M., Rezzi, S., Franceschi, C., & Collino, S. (2014). Serum profiling of healthy aging identifies phospho- and sphingolipid species as markers of human longevity. Aging, 6(1), 9–25.

[13] Cheng, S., Larson, M. G., McCabe, E. L., Murabito, J. M., Rhee, E. P., Ho, J. E., Jacques, P. F., Ghorbani, A., Magnusson, M., Souza, A. L., Deik, A. A., Pierce, K. A., Bullock, K., O’Donnell, C. J., Melander, O., Clish, C. B., Vasan, R. S., Gerszten, R. E., & Wang, T. J. (2015). Distinct metabolomic signatures are associated with longevity in humans. Nature communications, 6, 6791.

In Aging Cell, researchers have published a paper on a cellular energy source that appears to be a key signaling molecule in sarcopenia.

A little-explored molecule

Sarcopenia, a condition that increases with aging, reduces muscle mass in older people, and leads to a decreased quality of life [1], has been documented to have multiple root causes. Among them are signaling pathways, whose dysregulation affects the number and function of energy-producing mitochondria [2]. There are no approved treatments that directly affect these pathways.

Much research has focused on overall approaches that have been documented to positively affect sarcopenia, such as caloric restriction [3] and other metabolic interventions [4]. In particular, some research has found that a diet that induces ketosis is beneficial in combating muscle loss [5] and causes an increase in β-hydroxybutyrate (β-HB), as does exercise [6].

However, despite its association with interventions that reduce sarcopenia, β-HB itself has been little studied in this respect. These researchers hypothesized that this particular ketone body, which is both a signaling molecule and an alternative energy source [7], is potentially effective as a treatment for sarcopenia.

A key enzyme and a key pathway

To test their hypothesis, the researchers first investigated genetically diverse mice. The natural synthesis of β-HB is governed by an enzyme, HMGCS2, and more HMGCS2 leads to more β-HB. The size of the gastrocnemius, a major leg muscle, was correlated with HMGCS2 mRNA in these mice, as were the mRNA levels of two related enzymes. All three of these enzymes were found to decrease with aging in these mice. These findings were confirmed in primates, and trends towards these findings were found in human data.

The researchers then studied the mouse myoblast cell line C2C12, which is commonly used as a model of sarcopenia. Myosin heavy chain, a crucial protein for muscle use, is decreased with the administration of TNF-α, an inflammatory cytokine that increases with aging. Administering β-HB counteracted this effect, and it did not seem to affect cells that had not been exposed to TNF-α.

These encouraging results led to further experiments with mice. 23-month-old mice, near the end of their lifespan, were given either β-HB or a control for one month. The mice that received β-HB were able to run for longer, had larger muscles, and trended towards having more grip strength than the control group. They also had increased myoglobin, a protein required for muscle function.

Such findings were also replicated in C. elegans, a common worm model of aging. Worms tend to bend and move less with aging, but administering sufficient β-HB to older worms restored their function and encouraged the maintenance of muscle fibers. Increasing the worms’ production of β-HB through the worm analog of HMGCS2 yielded similar benefits.

A gene expression analysis found that cells given β-HB had more functional mitochondria in multiple respects, including additional energy production, better organization, and better use of oxygen. These findings were corroborated with a pathway analysis, which found similar upregulation in similar areas. Specifically, histone Kbhb was found to be crucial in the effects of β-HB, as blocking this histone nullified its positive effects. This same histone is upregulated in caloric restriction.

These findings open up an entirely new line of inquiry for drug discovery and potential treatments. While off-target effects and potential dangers have yet to be discovered, if aging muscle cells can be encouraged to produce more β-HB or histone Kbhb, it may be possible to significantly attenuate the frailty that comes with this crippling and dangerous disorder.

Literature

[1] ESPINOZA, B. S. M., RODRIGUEZ, A. S., CARRASCO, O. R., ROBLEDO, L. M. F. G., & FUNES, J. A. A. (2021). Sarcopenia Is Associated With Physical and Mental Components of Health-Related Quality of Life in Older Adults.

[2] Yin, L., Li, N., Jia, W., Wang, N., Liang, M., Yang, X., & Du, G. (2021). Skeletal muscle atrophy: From mechanisms to treatments. Pharmacological research, 172, 105807.

[3] Jang, Y. C., Liu, Y., Hayworth, C. R., Bhattacharya, A., Lustgarten, M. S., Muller, F. L., … & Van Remmen, H. (2012). Dietary restriction attenuates age‐associated muscle atrophy by lowering oxidative stress in mice even in complete absence of CuZnSOD. Aging cell, 11(5), 770-782.

[4] Hamrick, M. W., & Stranahan, A. M. (2020). Metabolic regulation of aging and age-related disease. Ageing research reviews, 64, 101175.

[5] Wallace, M. A., Aguirre, N. W., Marcotte, G. R., Marshall, A. G., Baehr, L. M., Hughes, D. C., … & Baar, K. (2021). The ketogenic diet preserves skeletal muscle with aging in mice. Aging cell, 20(4), e13322.

[6] Evans, M., Cogan, K. E., & Egan, B. (2017). Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. The Journal of physiology, 595(9), 2857-2871.

[7] Puchalska, P., & Crawford, P. A. (2017). Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell metabolism, 25(2), 262-284.