Mois : mai 2024

Researchers have found that removing senescent cells makes it easier for mice to fight initial infections but harder for them to develop immune memory.

Senescence and immunity

Introducing their paper, the researchers discuss the SASP and the relationship of senescent cells to the immune system, noting that “the aged microenvironment is one of the key drivers of dysfunction in CD4 and CD8 T-cell responses” and that CD8 T cells are responsible for clearing viruses. Additionally, with aging, CD4 cells fail to differentiate into the memory cells needed for long-term immunity [1].

These researchers had previously found that senolytics may have beneficial effects on the immune system, including rescuing CD4 T-cell differentiation [2], and others found that senolytics improve survival in mice against a coronavirus [3].

In an effort to identify causal relationships, these researchers employed aged, genetically engineered mice provided by Dr. Judith Campisi. These mice’s p16-expressing senescent cells can be removed by the administration of ganciclovir (GCV), which, itself, has no effect on the flu that was used to challenge their immune systems. However, some of the results showed a significant downside.

The mostly expected results

Shortly after having their senescent cells cleared, the mice also had a slight, non-significant decrease in the senescence marker SA-β-gal. Interestingly, they also had a similarly slight increase in the DNA damage marker γ-H2AX.

12 to 30 days after being exposed to influenza, the GCV-exposed model mice had cleared significantly more of the virus from their systems than the unexposed control group. This was traced to a decrease in CD127, a receptor for IL-7. T cells with more CD127 are more likely to survive after a virus and become memory cells. However, T cells with less CD127 are more likely to be involved in clearing the virus [4].

In other words, the upside and downside are closely connected: clearing p16-expressing cells improves short-term immune efficiency at the cost of long-term immune memory. This finding was heavily corroborated by further experiments with a different flu virus: the number of flu-specific memory T cells was significantly less than in the control group, and rechallenging those mice with the same flu again showed that their memory response was less effective.

However, these mixed results may be confined to p16-expressing CD8 cells. These researchers have done previous work on CD4 cells, targeting them with the senolytic combination of dasatinib and quercetin with positive results [2]. This serves as strong evidence that senescent cells, and their effects, are heterogenous and cannot be treated as a single factor.

Literature

[1] Haynes, L., Eaton, S. M., Burns, E. M., Randall, T. D., & Swain, S. L. (2003). CD4 T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly. Proceedings of the National Academy of Sciences, 100(25), 15053-15058.

[2] Lorenzo, E. C., Torrance, B. L., Keilich, S. R., Al‐Naggar, I., Harrison, A., Xu, M., … & Haynes, L. (2022). Senescence‐induced changes in CD4 T cell differentiation can be alleviated by treatment with senolytics. Aging cell, 21(1), e13525.

[3] Camell, C. D., Yousefzadeh, M. J., Zhu, Y., Prata, L. G. L., Huggins, M. A., Pierson, M., … & Robbins, P. D. (2021). Senolytics reduce coronavirus-related mortality in old mice. Science, 373(6552), eabe4832.

[4] Obar, J. J., & Lefrançois, L. (2010). Memory CD8+ T cell differentiation. Annals of the New York Academy of Sciences, 1183(1), 251-266.

In this latest edition of the Longevity and DeSci Recap, we’ll be taking a look back over a month full of events, research, and investments. As we head into spring, renewed life is on the horizon with continued investments in the longevity sector and the announcement of a permanent longevity/DeSci hub being launched on the sandy shores of the Caribbean.

Upcoming conferences and events

Global Synthetic Biology Conference

Spanning four days this May, the Global Synthetic Biology Conference will take place in San Jose, California, hosting 180+ content experiences, 20+ networking opportunities, and 200+ sponsors and exhibitors. This year, topics are set to include human health, planetary health, tools and technology, and the business of biology and society. Tickets for the event are available here.

SALT iConnections is coming to New York

This May 20-21, SALT, the global investment platform, will host an event centered on the impact of disruptive technologies on global finance, geopolitics and economics. Expected to be attended by prominent figures from New York’s financial ecosystem, the event offers a variety of sessions covering growth, innovation, and opportunities. Tickets are still available online.

Annual therapeutics summit returns

This June 11-13, the Age-Related Disease Therapeutics Summit is back for its sixth edition. Featuring 20+ speakers, works, and more, the event will host industry names such as Eli Lilly, Takeda, Turn Bio, BioAge, and Rubedo Life Sciences. Further info and tickets are available here.

Off to Dublin for the Longevity Summit 2024

From June 13-16, the capital city of the Emerald Isle will play host to one of the biggest longevity events of the season. This year’s conference will host talks on rejuvenation biotechnology and longevity, with speakers to include Dr. Irina Conboy and Matthew “Oki” O’Connor. Tickets are still available here.

11th Aging Research and Drug Discovery Meeting

ARDD is back in 2024 this August. This year’s event is set to delve into such topics as senolytics, stem cell research, healthy longevity, and epigenetic reprogramming with prominent industry speakers, such as Nir Barzilai, Vera Gorbunova, and Aubrey de Grey. Tickets and event details are available here.

Tech breakthroughs & new research

Gero combines wearable tech and longevity research in new study

Aimed at uncovering the digital biomarkers of aging through the use of wearable technology, Gero has announced the launch of a new study conducted through its GeroSense app. The company has launched a non-profit initiative that draws upon specific data, such as daily step patterns and heart rate, to help improve predictive accuracy for aging. The study seeks to uncover the relationship between such things as exercise, diet, mental health, and medication on aging in the context of human behavior.

$1 billion launch for AI drug discovery company Xaira

The season of biotech investment has arrived with the formation of Xaira, an AI drug discovery company. Backed by $1 billion in initial funding and investors such as ARCH Venture Partners and Foresite Labs, Xaira is set to emerge from stealth mode and tackle data scarcity within drug development studies with its AI platform.

Gordian Biotechnology reveals new platform for drug development

Launching with a $60 million investment, Gordian Biotechnology has announced a proprietary in vivo therapeutic screening platform. Designed to target age-related diseases by streamlining the process for drug development through technology, the company boasts up to 80% predictive power for illnesses such as heart failure and osteoarthritis. With similar approaches leading to drug discovery already yielding promising results, the team behind Gordian Biotechnology seek to accelerate the discoveries with enhanced efficiency.

DAOs and communities

Vitalia pop-up city event draws to a close — what’s next?

Community living with a longevity twist, Vitalia was the second of its kind, a pop-up city event focused on growing the longevity community and its governance, following the success of Zuzalu. Spanning the first four months of 2024, the pop-up city located on the Roatán island in Honduras hosted longevity enthusiasts, experts, and curious health seekers alike from all over the world. Now, due to its success, the organizers have announced that Vitalia now has a permanent hub on Roatan within the special economic zone of Próspera, an area that facilitates legal autonomy suitable for pioneering longevity research and start-ups. Lifespan.io’s Arkadi Mazin visited the city and tells of its potential now and in the future.

For people thinking of visiting over the next few months, here’s a taste of what’s on the schedule:

May 24-26 will see a focus on designing and building infrastructure for the DeSci community. With a move to the new Beta district planned, construction technologists, biomedical visionaries, and healthcare infrastructure builders are welcomed to attend.
Next up from June 18-22, medicine and biotech acceleration will come to the forefront with a deep dive collaboration into regenerative medicine and accelerated clinical trials.
July 26-28 will see biohacking take center stage as interested parties question “What does it mean to upgrade humanity?”

More events are planned till the end of the year, with the schedule constantly evolving. Stay tuned here and on the Vitalia website for the latest details.

DAOs for funding and collaborative development

As the concept of DAOs and their potential within the physical sciences grows, increasing research is being conducted and their impact recognized as a tangible solution. This latest article, published in Nature, highlights the potential of DAOs, challenges ahead, and their future role in life sciences, including VitaDAO as a case study.

Social media pages to follow this month

Research Hub Foundation offers the latest collaborations and crypto uses within the research sphere.

Longevity Summit Dublin provides the newest updates on one of the year’s biggest longevity conferences.

ValleyDAO delves into the wider ecosystem of longevity.

In a recent Pharmaceutical Research paper, the researchers explored the molecular processes through which the NAD+ precursors NMN and NR reversed ovarian aging in middle-aged rats [1].

Use it or lose it

Female fertility decreases rather quickly in life. Aging leads to a decrease in the number and quality of oocytes, and fertilization success declines in a woman’s 30s [2]. Therefore, multiple research groups have been aiming to attack the aging ovary problem from many angles.

The researchers of this paper focused specifically on how aging affects mitochondrial fragmentation (fission) and mitochondrial merging (fusion) mechanisms in ovaries. These processes are essential for proper mitochondrial functioning and mitochondria-dependent biological processes [3].

Previous research has shown that increased NAD+ levels can improve mitochondrial function and reverse ovarian aging [4]. Since NAD+ precursors, namely nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), are commonly consumed as supplements and have good safety profiles, these researchers determined that it was worth testing whether supplementing rats with NMN or NR can improve ovarian aging.

Better weight and better looks

The researchers compared four groups of rats, with each group containing six animals: young, middle-aged, middle-aged + NMN, and middle-aged + NR. The treated animals received MNM and NR for 17 days. The next day, researchers compared the animals’ biomarkers.

First, the researchers compared the body weight versus the ovarian weight of the animals to calculate the ovarian index, which is used as an indicator of female fertility. A high ovarian index indicates better fertility [5]. The results showed a slight increase in the ovarian index following NMN and NR treatments.

Researchers also looked into the morphology of the organ. They observed increased amounts of corpus luteum in the middle-aged rats treated with NMN and NR. The corpus luteum is a structure that forms in the ovary following ovulation. It secrete progesterone, a hormone essential for implantation and pregnancy [6]. Aging leads to a diminishment of the corpus luteum [7].

Another indication of the state of ovarian aging in the middle-aged rats that showed improvements upon NMN and NR treatments was the increased number of antral follicles and decreased number of atretic follicles. Follicles in the ovary are sacs that contain immature eggs. Antral follicles are large follicles that are preparing for ovulation, while atretic follicles are characterized by apoptotic bodies, a degenerating oocyte, and fragmentation of the oocytic nucleus [8].

Hormones are another essential component necessary for proper ovarian functioning and reproduction and are impacted by ovarian aging. Based on the rats’ luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio, the researchers learned “that ovarian aging disrupted the LH/FSH balance” and increased ovarian follicular atresia, a process of follicular degeneration or resorption accompanied by apoptosis. However, here again, NMN and NR applications improved those parameters: they helped to rebalance the LH/FSH ratio and decreased follicular atresia.

Mitochondria and sirtuins in service of better ovarian health

The previously described phenotypes are the usual suspects in ovarian aging. However, in this paper, the researchers also decided to investigate mitochondrial phenotypes as a marker of ovarian health since mitochondrial fission and fusion proteins are essential in oogenesis, embryogenesis, implantation, and protection of the ovarian follicular reserve [9, 10].

Compared to young rats, middle-aged rats had significantly reduced levels of gene transcripts of mitochondrial fusion-associated genes. NMN and NR treatment helped to increase the expression of those genes in middle-aged rats close to the levels seen in young rats.

The mitochondrial fission-associated gene transcript levels in middle-aged rats were increased compared to those in younger rats. NMN and NR treatment significantly reduced those gene levels in the rats’ ovaries. The protein analysis confirmed the positive impact of NMN and NR.

Seeing the connection between NMN, NR, and mitochondria prompted the researchers to test the levels of sirtuins. Sirtuins were previously reported to help delay ovarian aging and balance mitochondrial dynamics, and they are regulated by NAD+ [11]. Therefore, measuring their levels was essential in this experimental setup.

The researchers observed decreased levels of Sirt1 transcripts in the middle-aged group compared to the young rats, probably due to a decrease in NAD+ caused by aging. Treatment with the NAD+ precursors NMN and NR increased Sirt1 levels in ovaries. Those results were confirmed by measuring SIRT1 protein levels.

Bringing it all together and moving forward

Based on the current results and previous research, they hypothesized that NAD+ released from NMN and NR supplementation led to SIRT1 activation. Activated SIRT1 led to a decrease in DRP1, one of the fission-related proteins, which decreased the frequency of mitochondrial fission.

The authors point out that previous research on model animals and humans shows that NMN and NR supplementation is safe even at high doses. This is good news for future testing of NMN and NR supplementation in humans for delaying ovarian aging.

This study displays that […] the administration of a NAD+ precursor (NMN or NR) restores LH/FSH balance and mitochondrial dynamics, increases SIRT1 activity and alleviates folliculogenesis problems in middle-aged rats. Therefore, we consider that NMN and NR may be used as drug or supplement for reduction of aging-induced folliculogenesis or ovulation problems.

Literature

[1] Arslan, N. P., Taskin, M., & Keles, O. N. (2024). Nicotinamide Mononucleotide and Nicotinamide Riboside Reverse Ovarian Aging in Rats Via Rebalancing Mitochondrial Fission and Fusion Mechanisms. Pharmaceutical research, 10.1007/s11095-024-03704-3. Advance online publication.

[2] Amanvermez, R., & Tosun, M. (2016). An Update on Ovarian Aging and Ovarian Reserve Tests. International journal of fertility & sterility, 9(4), 411–415.

[3] Tilokani, L., Nagashima, S., Paupe, V., & Prudent, J. (2018). Mitochondrial dynamics: overview of molecular mechanisms. Essays in biochemistry, 62(3), 341–360.

[4] Yang, L., Lin, X., Tang, H., Fan, Y., Zeng, S., Jia, L., Li, Y., Shi, Y., He, S., Wang, H., Hu, Z., Gong, X., Liang, X., Yang, Y., & Liu, X. (2020). Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD+ redox. Aging cell, 19(9), e13206.

[5] Li, S., Liu, M., Ma, H., Jin, Q., Ma, Y., Wang, C., Ren, J., Liu, G., & Dai, Y. (2021). Ameliorative effect of recombinant human lactoferrin on the premature ovarian failure in rats after cyclophosphamide treatments. Journal of ovarian research, 14(1), 17.

[6] Taketa Y. (2022). Luteal toxicity evaluation in rats. Journal of toxicologic pathology, 35(1), 7–17.

[7] Acuña, E., Fornes, R., Fernandois, D., Garrido, M. P., Greiner, M., Lara, H. E., & Paredes, A. H. (2009). Increases in norepinephrine release and ovarian cyst formation during ageing in the rat. Reproductive biology and endocrinology : RB&E, 7, 64.

[8] Saatcioglu, H. D., Cuevas, I., & Castrillon, D. H. (2016). Control of Oocyte Reawakening by Kit. PLoS genetics, 12(8), e1006215.

[9] Liu, X. M., Zhang, Y. P., Ji, S. Y., Li, B. T., Tian, X., Li, D., Tong, C., & Fan, H. Y. (2016). Mitoguardin-1 and -2 promote maturation and the developmental potential of mouse oocytes by maintaining mitochondrial dynamics and functions. Oncotarget, 7(2), 1155–1167.

[10] Zhang, M., Bener, M. B., Jiang, Z., Wang, T., Esencan, E., Scott, R., Horvath, T., & Seli, E. (2019). Mitofusin 2 plays a role in oocyte and follicle development, and is required to maintain ovarian follicular reserve during reproductive aging. Aging, 11(12), 3919–3938.

[11] Iljas, J. D., Wei, Z., & Homer, H. A. (2020). Sirt1 sustains female fertility by slowing age-related decline in oocyte quality required for post-fertilization embryo development. Aging cell, 19(9), e13204.