Mois : mai 2024

Exercise may be able to remove senescent cells only if acute inflammation is allowed to occur, according to a new study published in Aging.

Inflammation and senescence

Inflammation is known to be a critical part of aging, and its chronic accumulation has been labeled as a hallmark of aging: inflammaging. The SASP, the cocktail of compounds that senescent cells emit, is a key contributor to inflammaging and drives other cells senescent.

However, there is published evidence that some inflammation works in the other direction. Senescent cells can be removed by immune cells known as macrophages [1], and immune system-based therapies have been investigated for therapeutic use [2].

These researchers have previously reported that p16INK4a, a well-known marker of cellular senescence, decreases in young men 24 hours after high-intensity exercise [3]. Moderate exercise, however, did not have the same effect. They hypothesized that even though chronic inflammation encourages senescence, acute inflammation that results in CD11b-positive immune cells entering tissues discourages it.

Stimulating inflammation with exercise

The researchers recruited a dozen young men (average age of 22 years old) with no history of smoking or drug use to test this hypothesis. Half of the participants were given 400 milligrams of the anti-inflammatory medication ibuprofen, and half were given placebo. The participants cycled at high intensity for 20 seconds and took a 20-second rest for 15 sets. Their muscles were biopsied before exercise and then again 3 and 24 hours afterwards.

After 3 hours, mRNA expression of p16INK4a was decreased in both the ibuprofen and placebo groups, although significantly more in the placebo group, suggesting that the anti-inflammatory effect was also preventing the clearance of senescent cells. This trend continued at the 24-hour mark. However, not all participants responded in the same way, and some participants had significantly more p16INK4a at the beginning of the experiment than others.

Interestingly, CD11b was also decreased by exercise, at a similar rate to p16INK4a. These results were also attenuated by ibuprofen administration. CD11b was found to be directly related to p16INK4a expression in the tissue. There was also a trend towards greater expression of the DNA damage marker γ-H2AX 3 hours afterwards in the ibuprofen group and less expression 24 hours afterwards, but these were not statistically significant.

A limited but possibly valuable study

The researchers note that the total amount of exercise needed to get the observed effects was very low and conducted in short bursts: 10 minutes of exercise resulted in effects that diminished over the course of a full day.

However, this experiment was conducted solely on a relatively small cohort of young men, so it is unknown if these results are applicable to older people or women. There was no follow-up to determine long-term effects. The markers CD11b, p16INK4a, and γ-H2AX were the only metrics used; other senescence biomarkers were not used. A significant amount of future work will need to be conducted to determine if these results apply to other populations and if these findings can be used to develop therapeutic treatments or call for a reduction in anti-inflammatory use with exercise.

Literature

[1] Kay, M. M. (1975). Mechanism of removal of senescent cells by human macrophages in situ. Proceedings of the National Academy of Sciences, 72(9), 3521-3525.

[2] Prata, L. G. L., Ovsyannikova, I. G., Tchkonia, T., & Kirkland, J. L. (2018, December). Senescent cell clearance by the immune system: Emerging therapeutic opportunities. In Seminars in immunology (Vol. 40, p. 101275). Academic Press.

[3] Jean, W. H., Hsieh, Y. W., Lai, L. F., Dewi, L., Liao, Y. C., Ye, M., … & Kuo, C. H. (2023). Senolytic effect of high intensity interval exercise on human skeletal muscle. Aging (Albany NY), 15(3), 765.

John Hancock, along with its Toronto-based parent company Manulife (NYSE:MFC), today announced a five-year, multimillion-dollar research collaboration with the Massachusetts Institute of Technology (MIT) AgeLab, a multi-disciplinary research institute that works with business, government, and NGOs, leading innovation and research to help improve the quality of life for the aging population and their loved ones. Over the next five years, Manulife/John Hancock and the MIT AgeLab will collaborate to research the future of longevity innovation, developing research, thought leadership, and workshops with the goal of driving actionable insights for the business community, policymakers, and individuals and their families.

The World Economic Forum (WEF) reports that by 2050, the number of people aged over 60 is expected to double to 2.1 billion. Yet, one-fifth of an individual’s life, on average, is now expected to be lived with morbidity or in a state of illness. Lifespans and healthspans are not evenly distributed at the national or global level: a significant outcome of socioeconomic and environmental disparities. As such gaps expand, so does the need for immediate action to address what is already a major longevity crisis in our communities and the world at large. As the aging population grows, better understanding the intersection of health and wealth, including preventative health measures and retirement planning, will be paramount.

“The fastest-growing age cohort in the world is people over 85. As we continue to see people live longer lives, it is crucial that we gain new insight into how we can make longer lives synonymous with better and healthier lives,” said Brooks Tingle, president and CEO, John Hancock. “We fundamentally believe in helping make this a reality and know that this ambition does not start and end within the walls of our business. That’s why we’re committed to collaborating with leaders in the space, like the MIT AgeLab, to help provide others—from policymakers to industry leaders to healthcare advocates—with critical learnings that can scale our shared mission to drive better health and wealth outcomes.”

This research will explore the critical tenets of longevity in the United States and hopes to develop a first-of-its-kind longevity preparedness index, to be produced annually over an initial five-year period. As lifespans continue to increase worldwide, the index will measure the readiness of Americans from every generation to live a longer, healthier, and better life; and provide data-driven insights for maximizing financial planning, health and wellness habits, work and retirement transition planning, housing choices, end-of-life planning, and technological advances that support critical health and financial needs at each step of the aging process. Research on the first annual index will begin in the spring of 2024. The index is expected to expand to include Canada as the collaboration evolves.

MIT AgeLab founder and director Dr. Joseph Coughlin will lead this work with a team of social and data scientists along with experts outside of MIT. In addition to the index, the group will host several workshops throughout the year to engage in discussions and activations around longevity, generational dynamics, new technology, and behavioral insurance. Manulife/John Hancock has also joined the MIT AgeLab PLAN, an industry consortium examining how the business of advice might better prepare people to live 100 good years.

“My research team is excited to embark on this research collaboration with Manulife/John Hancock,” said MIT AgeLab’s Coughlin. “The spirit of MIT is to think and do. We want not only to identify the many different dimensions of what it takes to live longer, better; but also to measure the preparedness of a nation to live 100 good years. It is our shared objective that our work will educate and motivate people to do what it takes for themselves, their families, and their communities—to turn a longer life into a better life for all.”

The MIT AgeLab, based within MIT’s Center for Transportation & Logistics, is known internationally for its multi-disciplinary work exploring avenues of pragmatic, actionable innovation desired by, and useful to, aging consumers and workers, as well as their loved ones. This ongoing project spans sectors including automotive, healthcare, caregiving, housing and community design, and financial services; and inspired Coughlin’s bestselling 2017 book, The Longevity Economy.

This announcement supports Manulife’s Impact Agenda, which seeks to empower sustained health and well-being, and builds on John Hancock’s inaugural Longer. Healthier. Better. Symposium  hosted in Boston in September of 2023, where global leaders across public and private sectors convened to share the latest research and innovations driving the future of longevity. Globally, Manulife was proud to support WEF’s recently announced Longevity Economy Principles, which offer a strategic approach to addressing the global longevity crisis. Manulife also recently announced a multi-year partnership with UpLink, WEF’s open innovation platform, designed to help shape the future of, and investment in, longevity innovation.

Learn more about Manulife, John Hancock, and the MIT AgeLab.

About John Hancock and Manulife 

John Hancock is a unit of Manulife Financial Corporation, a leading international financial services provider that helps people make their decisions easier and lives better by providing financial advice, insurance, and wealth and asset management solutions. Manulife Financial Corporation trades as MFC on the TSX, NYSE, and PSE, and under 945 on the SEHK. Manulife can be found at manulife.com. One of the largest life insurers in the United States, John Hancock supports more than ten million Americans with a broad range of financial products, including life insurance and annuities. John Hancock also supports US investors by bringing leading investment capabilities and retirement planning and administration expertise to individuals and institutions. Additional information about John Hancock may be found at johnhancock.com.

Experiments in mouse models show the efficacy and safety of mesenchymal stem cell transplantation in treating ovarian aging [1].

Mesenchymal stem cells as a therapy

Mesenchymal stem cells (MSCs) are stem cells derived from mesodermal tissue, such as the umbilical cord, umbilical cord blood, the placenta, fat tissue, and bone marrow [2]. MSCs are a promising new therapeutic approach for various diseases [3], including this paper’s focus: female infertility caused by ovarian aging.

The quantity and quality of oocytes start to decline relatively early in a female’s life. [4] Since contemporary women frequently postpone motherhood, the number of females diagnosed with infertility increases. [5]

At this moment, MSC therapy for human ovaries is in the preliminary stage of clinical application [6, 7]. Studies to date have focused on women with premature ovarian failure and ovarian hyporesponsiveness and used MSCs derived from their own bodies.

The efficacy of MSCs

The difference between this study and the previous mouse study is that in previous studies, stem cells were injected through the animals’ tail veins, which required cells to travel from the site of injection to the ovaries. In this study, the researchers used orthotopic transplantation, which allows the cells to be delivered closer to the site of their action to increase efficiency.

Among other groups, the researchers used young (4-5 months) mice and aged (10-12 months) mice, which had reduced reproductive functions, in order to evaluate the efficacy and toxicity of MSC treatment. MSCs were derived from healthy donors’ fat tissue (adipose tissue, AD) obtained during liposuction surgery and from full-term umbilical cord (UC) tissue following neonatal delivery. The researchers observed improved ovarian functioning in aging mice when AD-MSCs and UC-MSCs were used. However, AD-MSCs were shown to be more effective than UC-MSCs.

Following the injection of MSCs, the mice were monitored for eight days to track their oestrous cycle, the murine equivalent of monthly hormonal changes in human females. MSC transplantation improved this cycle compared to the control animals. For UC-MSCs, the changes in the duration of cycle phases were statistically significant, but for AD-MSCs, they were not.

After 1 and 3 weeks following the transplantation, the mice were sacrificed, and their tissues were analyzed. Analysis of the ovaries revealed that old mice that received AD-MSCs had a significantly increased proportion of proliferating cells compared to controls. UC-MSCs led to a slight increase in the proportion of proliferating cells, but it wasn’t statistically significant.

MSC ovarian transplantation didn’t increase the total number of follicles, which contain immature egg cells, in the ovaries. Still, the number of primary follicles significantly increased after UC-MSC and AD-MSC transplantation compared to controls. Also, both types of stem cells increased blood vessel proliferation in older animals’ ovaries.

An analysis of gene expression showed that UC-MSC and AD-MSC transplantation led to increased expression of MAPK cascade components, “central signaling pathways that regulate a wide variety of stimulated cellular processes, including proliferation, differentiation, apoptosis and stress response” [8]. AD-MSCs caused more changes in gene expression than UC-MSCs, including “cell-cell adhesion and positive regulation of the immune response.” The researchers also observed that these treatments had different short-term and long-term effects. While short-term effects involved different signaling pathways, “long-term effects were enriched in the activation of immune function.“

Good safety profile

Since the treatment’s efficacy showed promising results, the next step was to assess the safety of these transplants, which is indispensable in assessing theiir clinical utility.

Analyzing the mice sacrificed in this experiment indicated that they appeared healthy and that the transplanted MSCs did not generate tumors. Similarly, toxicity testing showed that “there was no significant acute toxic reaction” following MSC transplantation. Additionally, the expression of immune molecules wasn’t significantly increased, and the number of immune cells didn’t significantly increase in most mice. This data suggests that AD-MSC and UC-MSC transplantation does not significantly stimulate the immune system.

To function properly, orthotopically transplanted cells must reach their destination and not accumulate somewhere else in the body. The researchers injected a few mice with fluorescently labeled cells, and then searched the mice’s organs for these clearly visible cells after sacrifice. These cells accumulated mainly in the ovaries, with a small number of cells also observed in the uterus and spleen.

Therapy that holds potential

Based on the results of their experiments, the authors believe that MSCs hold great potential for clinical applications. Since they can be produced industrially, they can benefit many patients. However, first, the efficacy and safety of MSCs need to be shown during clinical trials.

Safety validation experiments confirmed that both AD-MSCs and UC-MSCs were not tumorigenic, with no acute toxic reactions, low immunogenicity, and a small amount of nondeterministic distribution. Furthermore, the mechanisms underlying the long-term and short-term effects after MSC transplantation differed, yet both led to an enhancement of the MAPK cascade. Collectively, orthotopic transplantation of MSCs has significant efficacy and high safety in the treatment of ovarian ageing.

Literature

[1] Pei, W., Fu, L., Guo, W., Wang, Y., Fan, Y., Yang, R., Li, R., Qiao, J., & Yu, Y. (2024). Efficacy and safety of mesenchymal stem cell therapy for ovarian ageing in a mouse model. Stem cell research & therapy, 15(1), 96.

[2] Kouroupis, D., Sanjurjo-Rodriguez, C., Jones, E., & Correa, D. (2019). Mesenchymal Stem Cell Functionalization for Enhanced Therapeutic Applications. Tissue engineering. Part B, Reviews, 25(1), 55–77.

[3] Galipeau, J., & Sensébé, L. (2018). Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell stem cell, 22(6), 824–833.

[4] Secomandi, L., Borghesan, M., Velarde, M., & Demaria, M. (2022). The role of cellular senescence in female reproductive aging and the potential for senotherapeutic interventions. Human reproduction update, 28(2), 172–189.

[5] Carson, S. A., & Kallen, A. N. (2021). Diagnosis and Management of Infertility: A Review. JAMA, 326(1), 65–76.

[6] Herraiz, S., Romeu, M., Buigues, A., Martínez, S., Díaz-García, C., Gómez-Seguí, I., Martínez, J., Pellicer, N., & Pellicer, A. (2018). Autologous stem cell ovarian transplantation to increase reproductive potential in patients who are poor responders. Fertility and sterility, 110(3), 496–505.e1.

[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] Plotnikov, A., Zehorai, E., Procaccia, S., & Seger, R. (2011). The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochimica et biophysica acta, 1813(9), 1619–1633.