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Cellular Senescence: It’s Complicated, but There’s Hope

This review outlines just how much these cells do to our bodies.

Research fundamentalsResearch fundamentals
 

Two of the most prominent experts in the field have published a review of cellular senescence in the context of metabolism, and we bring you the highlights [1].

We rarely cover review papers, but when Cristopher D. Wiley and Judith Campisi, two of the most prominent experts on senescent cells, publish a review on senescence and metabolism, we are happy to make an exception.

Senescent cells: helpers or traitors?

Senescent cells are cells that stop dividing but do not undergo death and removal from the organism. Such cells acquire altered morphology and linger in the body, releasing a complex of mostly pro-inflammatory chemicals called the senescence-associated secretory phenotype (SASP). Senescence can be induced by various types of stress, including replicative (after numerous divisions), genomic (DNA damage), radiation, and chemical. Senescent cells accumulate in our tissues with age and have been linked to multiple age-related disorders. For instance, SASP is probably a major factor in age-related systemic inflammation (inflammaging) [2].

Cellular senescence is not 100% bad, although the related biochemistry is complicated. Senescence is a powerful mechanism that inhibits carcinogenesis. It also plays an important role in wound healing. Wiley and Campisi note that cellular senescence might be an example of antagonistic pleiotropy, in which a mechanism that is beneficial earlier in life becomes deleterious in advanced age. Thus, it escapes evolutionary pressure, as nature doesn’t care what happens to you after you stop reproducing. In young organisms, the anti-cancer and regenerative effects of cellular senescence probably far outweigh its drawbacks, but as the burden of senescent cells grows with age, their darker side starts to dominate.

Cellular senescence was discovered back in the 1960s, but it is so complex a phenomenon that even today, many questions remain unanswered. As the authors note, senescence phenotypes vary between tissues, and no pathway of senescence is like another. The SASP has many variations as well [3]. This new review published in Nature seeks to make some sense of the complex relationship between cellular senescence and various aspects of our metabolism.

Causes of senescence

First, the authors discuss various causes of senescence, starting with mitochondrial dysfunction. Senescence caused by it has its own unique profile and name – mitochondrial dysfunction-associated senescence (MiDAS). It also results in a distinct SASP.

The authors mention that phenotypes of cellular senescence also depend on the oxygen available in the cell. This is easy to overlook in research, particularly when working on cell cultures subjected to room air, where oxygen concentration is higher than in tissues. As a rule, higher oxygen levels promote senescence, although it has been shown that hyperbaric therapy lowers markers of senescence in peripheral blood mononuclear cells. Hence, it is important to account for oxygen levels when studying senescent cells.

NAD+ is a compound that gets a lot of attention in the longevity field. Its age-related loss appears to be a major driver of senescence. Moreover, the authors suggest that SASP that seeps into the intracellular environment can trigger additional loss of NAD+ by interacting with macrophages. This creates a vicious cycle that can explain why age-related NAD+ loss is so harmful.

Hyperglycemia has also been identified as a major driver of senescence, though scientists still do not know how this works, since there are many potential mechanistic explanations. It is possible that, just like NAD+ deficiency, hyperglycemia drives senescence via loss of sirtuins. The authors note that “the links between diabetes and senescence are growing and increases in senescent cells at sites of diabetic complications indicate that this is an important area for future research.”

The metabolism of senescence

Moving to the metabolism of senescent cells, the authors note that there is a growing body of evidence that senescence considerably alters lipid processing in cells. In general, metabolic breakdown of lipids is upregulated in senescent cells since it is needed to produce many SASP components. In some types of senescent cells, particularly in the brain, lipid droplets are known to accumulate.

Research shows that lowering lipid levels in cell culture media prevents both lipid droplet accumulation and the upregulation of many SASP factors. Per the authors, this suggests that “lipid droplets, or at least the presence of lipids, is required for some key aspects of cellular senescence and the SASP”.

Another important process associated with cellular senescence is autophagy, the breaking down and recycling of organelles and macromolecules inside a cell. Autophagy is disturbed in senescent cells, and its inhibition has been shown to induce senescence. On the other hand, in line with the dual nature of senescence, activation of autophagy is a possible driver of some types of senescence.

Lysosomes, the organelles where autophagy takes place, are also dysregulated in senescent cells. Lysosome dysregulation increases acidity inside the cell, but senescent cells have ways to counter this. The authors propose to explore this pathway as a possible senolytic – basically, to help lysosomes kill senescent cells via increased acidity.

Possible interventions

This brings us to the last part of the review, which is dedicated to potential metabolic interventions. First, the authors describe the role of senescent cells in diabetes: according to them, senescent cells are responsible for several complications of diabetes, which means that some senolytics should also have anti-diabetic effects.

Statins, the drugs of choice against hypertension, in addition to lowering blood pressure, also inhibit many pro-inflammatory aspects of the SASP in fibroblasts and prevent senescence in endothelial progenitor cells. This may partly explain statins’ efficacy against atherosclerosis, since the latter is associated with senescence. Hence, it should be possible to use statins as senolytics outside the context of atherosclerosis.

An honorary mention goes to metformin, an anti-diabetes drug that has been shown to increase healthspan and lifespan in model organisms (read our interview with Nir Barzilai about the upcoming metformin study in humans). Metformin is known to protect against senescence in some cell types in vitro, along with murine models of intervertebral disc degeneration and chronic kidney disease. This might explain a lot of metformin’s hailed anti-aging qualities.

Finally, the authors mention two kinds of interventions that most of us can start applying right now: dietary changes and exercise. Caloric restriction, widely regarded as having anti-aging effects, prevents senescence in the kidneys of aged animals, while a high-calorie diet increases senescence. According to the review, ketogenic diets have been found to reduce markers of senescence in vascular smooth muscle cells and endothelial cells.

As for exercise, it is known to prevent senescence in hearts, livers, and adipose tissue of aged mice, and it has been linked to reduced markers of endothelial and leukocyte senescence in humans.

Conclusion

Cellular senescence is a multifaceted phenomenon, and its interplay with various functions of the body is far from being fully elucidated, as evidenced by this major NIH effort to create an atlas of senescent cells. Senescence can be both beneficial and deleterious, and its phenotypes vary among tissues. Hence, attempts, such as this review, to systematize our vast but insufficiently deep knowledge of cellular senescence are very important.

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Literature

[1] Wiley, C. D., & Campisi, J. (2021). The metabolic roots of senescence: mechanisms and opportunities for intervention. Nature Metabolism, 1-12.

[2] Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathology: Mechanisms of Disease5, 99-118.

[3] Wu, S. K., Ariffin, J., & Picone, R. (2020). The Senescence-Associated-Secretory-Phenotype induced by centrosome amplification constitutes a pathway that activates Hypoxia-Inducible-Factor-a. bioRxiv.

About the author
Arkadi Mazin

Arkadi Mazin

Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span from politics to science and philosophy. Having studied economics and international relations, he is particularly interested in the social aspects of longevity and life extension. He strongly believes that life extension is an achievable and noble goal that has yet to take its rightful place on the very top of our civilization’s agenda – a situation he is eager to change.
  1. michael1
    October 27, 2021

    “Statins, the drugs of choice against hypertension”? Statins lower LDL cholesterol. If they lower blood pressure is uncertain but I don’t think that they prescribed for this purpose.

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