Mois : décembre 2024

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.

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.

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.

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.

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.