Senescence: Aging Cells That Drain Youth?

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What is senescence? How does it affect the cells in organisms? How does it affect health?  Should humans accept senescence as a natural form of aging, or do we fight it to stay young? We will get into the phenomenon of senescence and its relationship to the lifelong-and perhaps bittersweet-odyssey of aging.

Senescence is a lifelong journey for humans, starting at birth

Senescence is a lifelong journey for humans, starting at birth

What is senescence?

Senescence or biological aging is the gradual deterioration of function characteristic all lifeforms age. Whether mammals, plants, or single-celled creatures -if it has cells, aging is the unavoidable one-way street starting at birth and ending at death. While we can’t speak for other lifeforms, when human get into “age talk,” it tends to provoke certain…contention. If you don’t believe it, ask yourself if at least once in your life you have heard these phrases: “Age is but a number”, “You’re only as old as you feel”, “Youth is wasted on the young!”

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These little quips you may hear from your elders might have a deeper meaning in our society: a defiant, or even bitter resolution towards old age. Now, pair all those phrases with the advertisements that inundate our screens: anti-aging creams, hair dye, plastic surgery, chemical peels and you get a sense that we rage a very intense and expensive war against the physical hallmarks of age.

But hallmarks are merely the surface of it; what exactly is this process we are fighting? Even with the knowledge that getting old is inevitable, it is worth exploring the roots of aging-and understanding that it is part of a deeper and ever so mysterious process known as senescence. Senescence is a phenomenon constantly investigated in the field of science, especially in disease research. We will delve into that more to see why It is so important a health topic.

Aging vs. Senescence

Aging and senescence are used interchangeably on a daily basis. To make the distinction: aging is a broader term for the functional decline in organisms over time. For mammals like humans, the aging process varies in how it manifests from person to person, but it has biological, psychological, and environmental implications. Senescence is tied to the biological aspect of aging: it is a process in which the body’s cells cease to divide and stay in a state of permanent growth without dying (apoptosis.)  Because senescence is associated with age-related changes in our health, senescence is conceptualized as “biological aging.” Let us get into the meaning of that.

Senescence: Aging Cells That Drain Youth?

Senescence is all about the biological process of aging.

Senescence Explained

“Cell senescence” is a term you will hear used to discuss the biological function of aging. It is described as a cell’s stress response to stop growing, and for cells that means dividing further in the body. “Stress” in this case is not the overworked and underpaid kind. Rather, the stress response is to “oncogenic stimuli,” meaning factors in the body likely to cause cellular crisis leading to tumors. Oncogenic stimuli manifest in many ways: mitochondrial dysfunction, telomere damage, DNA damage, and epigenomic disturbances.

  • Mitochondrial Dysfunction: Mitochondria are the organelles found in most cells and can be described as the cell’s “powerhouse.” Functioning mitochondria will complete several tasks: creating ATP (the cell’s energy source,) regulating the uptake of oxygen, regulating membrane potential, etc. As aging occurs, mitochondria can stop performing these essential tasks and this dysfunction becomes a trigger for senescence.
  • Telomere Damage: DNA molecules cannot completely replicate, because with each division of cells the ends of these linear structures get truncated. These truncated ends are made from DNA proteins called telomeres. Certain mammals like mice have an enzyme known as telomerase that helps prevent ends from being shortened in DNA replication. However, telomerase tends to be lacking in adult human cells, and therefore the truncation is inevitable. The shortening leads to a sort of “DNA repair” crisis that could cause tumorous growth, and senescence is the response to prevent that.
  • Genomic Damage: While mitochondria and telomeres are often the site of damage leading to senescence, it should be noted that any DNA damage can cause the senescent response. Oxidative stress and other DNA damage may cause lesions and breaks in the gene’s single and double strands, which cells will attempt to repair through senescence. Also, certain kinds of chemotherapy can be damaging to DNA and induce senescence in tumorous cells. It is important to note that all this damage can be interlinked with the dysfunction already seen in telomeres and mitochondria.
  • Epigenomic Damage: While we understand that traits are passed down through our parents’ genes, epigenetics has to do with such inheritable traits that do not involve changes to the DNA structure. Such processes involve transcription networks in the cells as well as a combination of DNA, RNA, and protein molecules known as chromatin that helps to package DNA. Changes to chromatin and transcription networks are the sort of epigenomic dysregulation that may induce cell senescence.

Senescence: What happens?

So, after exploring the causes of senescence in cells we wonder: what exactly happens to the affected cells? The changes that the cell undergoes can be described as the cell becoming “senescent” or perhaps simply, “aging” due to the influences we discussed. While these mechanisms cause senescence, it is the combination of the mechanisms and senescent cells that make up the aging process and cause some of the physical hallmarks of aging that we will get to later.

What makes senescent cells distinct from other processes that happen in the life cycle is that it is largely considered an irreversible process in age. Some cells do enter a state of cell cycle arrest, in response to certain growth inhibition. However, these cells-called “quiescent”-can eventually revert to the cell-cycle growth when the right conditions are restored. There is also a cellular process known as “terminal differentiation” that involves a permanent end to the cell cycle. Unlike senescent cells, however, in terminal differentiation, the cells go through extreme functional and morphological changes that cause the cells to lose their original identity. In summary, senescent cells are characterized as replicate-capable cells that stop growing permanently, while retaining their original identity.

You would be quite correct: the working theory of why we enter this senescent state is that the body is naturally trying to combat the formation of tumors that cause cancer, one of the most frequent non-communicable diseases in advanced age.

This theory goes all the way back to when the term “senescence” was first identified in 1961 by two scientists, Leonard Hayflick and Paul S. Moorhead. In their publication “The serial cultivation of human diploid cell strains,” they identified senescence as a response to prevent human lung fibroblasts (a type of connective tissue) from being populated and expanding. Later studies would make the link between arrested cell growth and aging. The response was shown to be specifically induced to stop cancer from proliferating.

Benefits of Senescence

Initial research seemed to show that the key benefit of cells that enter the senescent state is tumor suppression in mammals. Senescence causes the creation of cytokines, chemokines, and proteases, which together are classified as a senescence-associated secretory phenotype (SASP). SASP has the property of suppressing tumors as well as tissue repair. Mouse model studies have shown the benefits of senescent cells in stopping tumor growth. Telomerase in mice prevents the shortening of telomeres that so often leads to the genesis of tumors. When mice have the telomerase enzyme knocked out, they have been observed to enter a state of premature aging and cancer development associated with cells become senescent.

Wound repair also seems to be a benefit of senescence. When the senescent network p16INK4a is activated in wounded mice, healing is induced. There is still debate about how the network activation may heal damaged tissue in humans, but there is some evidence that the senescence-associated secretory phenotype (SASP) brings together healing.

Another unusual benefit of senescent cells is its suspected role in embryonic development. We are quite a long way from old age when we talk about the embryo-but there are indeed studies showing that cells with senescent features help shape the embryo and spark the genesis of human organs. These senescent cells are distinct from aging cells that depend on the networks that terminate proliferation. Thus, this type of cell senescence is put in its own category, developmental senescence.

Consequences of Senescence

Strange…we have discussed how senescence helps prevent cancer, so now we are talking about consequences? Well, the truth about this topic is that it is frustratingly complex, and scientists in the field of age research are making new and unsettling discoveries every year. What is clear is that senescence brings about some less than desired complications in the body. Ironically, one of the consequences of SASP-the senescent response to aging is that it can create a sort of harbor for certain other cancers to grow. Senescent cells may also accumulate in tissue to cause an increase the risk of cancer as we age; in fact, defeating its own purpose. Since senescent cells essentially stop growing and remain in this permanent state, certain building cells, like T-cells or pancreatic cells can lead to severe tissue degeneration if affected by the senescence.

In some ways senescence work in parallel with the very factors that induce it, to cause aging and age-related diseases. Several hallmarks of the aging process in humans have been shown to be a direct result of senescent cells, including proteostatic dysfunction (Huntington Disease, Alzheimer’s disease, cystic fibrosis), stem cell exhaustion, chronic inflammation, and nutrient signaling dysfunction. Again, all these consequences of senescence are in of themselves associated with diseases of advancing age; a mixed blessing that is the biological aging process.

Further studies of aging have shown that senescence may be implicated in several other diseases:

  • Renal dysfunction: Older age is often associated with diseases of kidney failure, and the gene expression associated with the failure is the same gene that provokes the tumor suppression of senescent cells. In addition, a 2016 study showed that ablating senescent cells in aging mice would improve their kidney function.
  • Type 2 diabetes: This type of diabetes is associated with the INK4 gene expression that is found in senescent cells. Certain senescent markers were elevated in beta cells of diabetic mice.
  • Cardiovascular disease: Atherosclerosis is a buildup of arteries that has been shown to be reduced when senescent cells are ablated.
  • Fatigue: Asthenia is a form of fatigue caused by chemotherapy. Certain chemotherapeutic treatments can cause senescence, specifically therapy-induced senescent cells. A 2017 study used a mouse model to show that the elimination of therapy-induced senescent cells was associated with mice regaining vitality. This evidence points to senescence being a contributor to fatigue in cancer patients.
  • Other diseases and phenotypes: Senescence is now being identified as an influence on other diseases and characteristics associated with aging. Graying hair, sarcopenia, adiposity, and glaucoma are all age-related hallmarks that are now believed to be in part driven by senescence. The explanation is that the expression of the senescent networks induces a variety of these age problems. It is the hope of most researchers that such senescent cells can be eliminated in mouse models to curb age problems.

So what’s the verdict on senescence?

This might be a fair question to pose to Dr. Judith Campisi, who is at the forefront of senescence research at the Buck Institute for Research on Aging. Most of the recent studies about age-related diseases from senescence are under the authorship of Dr. Campisi and her colleagues. From her discussions, senescence is a valiant attempt of our body to fight cancerous damage, and yet it also shepherds in age-related disease and deterioration. Her goal is to maximize the benefits of senescent cells while eliminating their consequences.

In attempting this, Campisi and other researchers are tackling a bold feat of locating a fountain of youth- or at least a fountain of healthier living. Preventing the development of senescent cells may indeed extend life for humans longer. The key is to prevent age-related diseases from manifesting because of senescence so that we can enjoy life without restriction. Treatments are now focused on eliminating senescent cells while decreasing the risk of developing cancer they are trying to prevent; drugs known as senolytics show promise in clearing senescent cells, but there is some concern of unintended side effects.

If science could take us as far as reversing the irreversible process of senescence, could we end up reverse the aging process? This is indeed a possibility, but it is truly beyond the scope of what has been observed in both human and animal studies. The senescent state does not seem capable of being reversed by any artificial means, and studies are more concerned with eliminating the harmful types to extend the lifespan. That is not to say there won’t be future attempts to target senescence to restore youth. But with the current direction in research, we may just need to come to peace with our impending gray hairs and live with the fact that age is “but a number.”

References

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Campisi, J., & D’Adda Di Fagagna, F. (2007). Cellular senescence: When bad things happen to good cells. Nature Reviews Molecular Cell Biology, 8(9), 729–740. https://doi.org/10.1038/nrm2233

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