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Cellular Senescence – a Key to Better Aging

April 29, 2022*

As we age our body more and more resembles a dumpster cut off from the waste system.  Cells are piling up that refuse to do their original job, which is either renew or die. In medicine this process is called senescence from the Latin word senescere – to age.
Normally, autophagy – the cell’s housekeeping – removes and replaces damaged or old cells. These cells would give off signals to the immune system to come and clear them out, and to make room for healthy cells. But in aging even immune cells weaken and become senescent. And when these inactive cells accumulate, the proteins that alert the immune system can trigger chronic inflammation and damage cells nearby.
From their initial discovery in the 1960s by Hayflick and Moorhead, researchers have regarded the “zombie”- state of senescent cells as a defense mechanism against tumor mutations. Over the years, scientists have linked senescence to age-related disorders like diabetes, cardiovascular disease, stroke, osteoporosis, Alzheimer’s disease, dementias and cancers. They believe that eliminating or reversing cellular senescence and boosting autophagy can lead to healthier aging. Yet so far, they have only been able to show rejuvenating effects in mice – and medical therapies or lifestyle recommendations for humans are still in their infancy.

“Senescent cells have very positive and beneficial functions,” said Dr. Marco Demaria in an online interview at his lab in Groningen, the Netherlands. “And it depends really on the context, time, environment or many other factors to say whether these senescent cells can be good or bad.”

“Senescent cells have very positive and beneficial functions” 

Dr. Marco Demaria

Demaria is a professor and group leader at the European Research Institute for the Biology of Ageing in Groningen, and the new president of the International Cell Senescence Association. In a 2020-medical review on senescence and aging together with other authors from his institute in Groningen, he wrote that in pregnancy, for example, short-term or local senescence supports the embryo’s organ growth. Senescent cells promote wound healing by clearing out damaged tissue. Senescence is also a potent tumor suppressor mechanism, as cells with cancer mutations can become senescent and stop spreading.
By contrast Demaria said that, “senescent cells are bad because when they accumulate, they persist and create chronic inflammation,“ and they build an optimal environment for diseases like rheumatoid arthritis or multiple sclerosis, and for cancer formation.

Senescence in aging, cancer and mitochondria
Senescence, and mechanisms of aging and cancer on the cell level are Demaria’s specialization. “I lost my father when I was quite young because of cancer, and eventually I think that is also why I started cancer biology,” he said in the interview. Working on cancer metabolism during his doctorate in Italy, he recognized that, “Eventually what you do in cancer is that you are just trying to kill the cancer cells and you don’t care much about their environment.”
Pioneering work from the Buck Institute for Research on Aging in California – the lab he joined as a postdoc – became what he called “mind blowing”: Senescent cells seemed to be part of the tumor environment – and they secret harmful proteins and inflammatory factors – a state named senescence-associated secretory phenotype (SASP). Normally SASP promotes tissue repair and regeneration and encourages our immune system to work properly. Still, it can be harmful, for example in aging or in cancer metastasis.
Among the reasons why healthy cells become senescent and stop their cellular function is a process called immunosenescence – the aging of the immune system.
Adjunct professor Dirk Mielenz is a group leader of immunology at Friedrich-Alexander-University Medical School in Erlangen, Germany, and the lead author of a recent publication on the senescence of the mitochondria –– and in B lymphocyte immune cells in particular.
In an interview at his lab in Erlangen he said that during energy production in the mitochondria – the cell’s power plant – oxygen molecules become unstable and produce harmful chemical oxidation, called reactive-oxygen species (ROS). The mitochondria are not only the major source of ROS, but also the main target of oxidative damage.

“It’s like what oxidation does in everyday life, it makes a bicycle chain go rusty, for example,” Mielenz said in German, “and you don’t want that in your cells either.“

Still, a certain amount of oxidative stress – a so-called oxidative burst – from immune cells is beneficial. It kills harmful proteins and spurs cell growth – but “too much oxidative stress can harm the DNA, and especially the mitochondrial DNA, worsening the development of tumors or rheumatic diseases, such as rheumatoid arthritis,” Mielenz said.

Can fasting counteract harmful senescence?

Given that oxidative stress is not all bad, Mielenz doubts the purpose of lifestyle interventions like “drinking some red wine or eating dark chocolate.” In current research, these so-called polyphenols are considered as potential anti-inflammatory nutrients against cell damage.
The essence of most anti-senescence strategies is that they can counteract the “nine hallmarks of aging”. They were defined in a 2013-medical review published in the journal Cell by Carlos López-Otin and colleagues. In this landmark paper, the researchers described a sequence of cell-damaging events as a general cause of aging. In this process, our cell’s genome destabilizes, telomeres – the cap endings of chromosomes – shorten, epigenetics alter and proteins weaken. Next, the cell’s nutrient-sensing declines, mitochondria fail, and cells become senescent. Finally, stem cells get exhausted and communication between cells fails. “It all comes down to senescence,” Demaria said, “because all hallmarks are highly related to senescence itself.”

Lifestyle habits like smoking, stress, skin exposure to sunlight, nutrition and physical activity can all harm our cells. “There are some lifestyle approaches, such as fasting mimicking diet or calorie restriction that modulate the same pathways that seem to be dysregulated in senescent cells,” Demaria said.
Intermittent fasting – that is limiting meal intake to a certain time slot per day (such as six to eight hours) – is a way to boost autophagy as the clearing process in the cell. The theory behind fasting is that in times when your body gets enough nutrients, it builds new cells and tissues. In fasting, on the contrary, autophagy starts and breaks down old cells or recycles proteins for future use.

Polyphenols and senolytic drugs
Certain polyphenols might have a positive effect on delaying the accumulation of senescent cells, Demaria said. “On the other side, it’s too difficult to intake the various nutrients simply by food or beverages. Stupid example: There has been the hype of resveratrol in red wine … and it means that you should drink around fifty bottles of wine a day.”
Natural based compounds like polyphenols are widely available in tablet form or in anti-aging cosmetics, although results from current evidence-based studies on patients are still pending. In a clinical setting, a strategy to prevent senescence could be using drugs that selectively kill senescent cells. In parallel, compounds have been identified that prevent or slow down the progression of senescence. At present in the U.S. alone, 771 clinical trials are open for participants to take part in intervention studies on senescence. So far, therapies have shown efficiency in mice, but unwanted dose-dependent side effects like toxicity still exist. In the U.S., for example, the National Institutes of Health have not yet confirmed the safety of so-called senolytic drugs.
Demaria’s wants to continue researching the good and bad of senescence, and if distinct types of senescent cells exist. “What excites me most at the moment is trying to understand how to distinguish between beneficial and detrimental senescence…or are we actually looking at two different things and we just put everything in one part and define it as senescence?”

References and further reading:

Borghesan, M., Hoogaars, W., Varela-Eirin, M., Talma, N., & Demaria, M. (2020). A Senescence-Centric View of Aging: Implications for Longevity and Disease. Trends in Cell Biology, 30(10), 777–791.

Hayflick, L., & Moorhead, P. (1961). The serial cultivation of human diploid cell strains. Experimental Cell Research, 25(3), 585–621.

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. Cell, 153(6), 1194–1217.

Shetty, A. K., Kodali, M., Upadhya, R., & Madhu, L. N. (2018). Emerging Anti-Aging Strategies – Scientific Basis and Efficacy. Aging and Disease, 9(6), 1165.

Urbanczyk, S., Baris, O. R., Hofmann, J., Golombek, F., Castiglione, K., Meng, X., Bozec, A., Mougiakakos, D., Schulz, S. R., Schuh, W., Schlötzer-Schrehardt, U., Steinmetz, T. D., Brodesser, S., Wiesner, R. J., & Mielenz, D. (2021). Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells. bioRxiv.

Yessenkyzy, A., Saliev, T., Zhanaliyeva, M., Masoud, A. R., Umbayev, B., Sergazy, S., Krivykh, E., Gulyayev, A., & Nurgozhin, T. (2020). Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research. Nutrients, 12(5), 1344.

*I wrote this feature for my capstone semester at Harvard University, therefore it might not comply with state-of-the-art research findings in the field of cellular senescence.

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