Senescence is a response to stress in which damaged cells terminate normal growth cycles to prevent dysfunctional cells from reproducing. Senescence is a vital cellular process involved in embryonic development, wound healing, and cancer immunity; [1] however, the accumulation of senescent cells is associated with diseases of aging such as cancer, cardiovascular disease, type 2 diabetes, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, sarcopenia, and glaucoma.[2] [3]

The immune system has an effective process for clearing senescent cells; however, many lifestyle factors that are common in the modern world impair the immune system's ability to maintain a safe concentration of dysfunctional cells. Research suggests that the following environmental factors increase the burden of senescent cells:

  • High glycemic diet: High blood sugar levels increased the rate of senescence in bone marrow-derived endothelial progenitor cells, a type of stem cell.[4]
  • Sedentary lifestyle: Exercise reduced the burden of cellular senescence in adipose tissue of mice fed a fast-food diet.[5]
  • Poor sleep: Poor sleep reduced the length of telomeres, the protective caps on the end of DNA strands, a type of DNA damage that increases senescence.[6]
  • Social stress and poverty: Chronic social stress increased the signature of cellular senescence among cells in multiple organs and reduced lifespan in mice.[7]

In addition to lifestyle factors such as nutrition, physical activity, sleep, and stress, senolytic drugs are being investigated for their capacity to reduce the body's burden of senescent cells due to aging. So far, researchers have identified the following compounds as senolytics:

  • Quercetin and dasatinib in combination reduced cellular senescence in adipose tissue among patients with diabetic kidney disease.[8]
  • Fisetin selectively induced apoptosis in senescent cells but not stem cells in vitro.[9]
  • Spermidine supplementation suppressed senescence in epithelial cells in mice when challenged with bleomycin, which causes oxidative stress. [10]
  • Navitoclax increased clearance of senescent chondrocytes in an in vitro model of osteoarthritis.[11]
  • Piperlongumine induced senescence and clearance of metastatic castration-resistant prostate cancer cells, reducing their ability to migrate and reproduce.[12]

Although senolytic drugs hold a lot of promise for anti-aging treatments in the future, they may also pose a risk to health if misused. Senescence expert Dr. Judith Campisi, had this to say about the safety of senolytic drugs compared to lifestyle interventions.

"mTOR dampening drugs suppress the ability of the senescent cells to secrete...If you were to fast for four days going to every few weeks, you might have more benefit, certainly more benefit than taking a drug like rapamycin, which has side effects."

Mechanisms of senescence

Senescent cells produce many chemical messengers to communicate their damaged state to neighboring cells. Researchers characterize senescent cells by the types of molecules they produce (e.g., proinflammatory cytokines, growth factors, enzymes, and lipids[13]), called a senescence-associated secretory phenotype (SASP). The profile of chemical messengers secreted by senescent cells is, in part, determined by the type of stress that has occurred.

Replicative senescence occurs when a cell has reached its capacity for replication. Most somatic (i.e., not germ cells such as sperm and egg cells) cells are programmed for this fate and will eventually enter replicative senescence if they don't undergo premature senescence due to injury.[14] Characteristics of replicative senescence include increased cell size, increased number of lysosomes (i.e., organelles that remove cellular waste), and secretion of enzymes that break down cells.[14]

This breakdown of cellular and extracellular structures by enzymes such as proteases and collagenases is essential for remodeling tissues after an injury. For example, fibroblasts are specialized wound-healing cells that migrate to the site of an injury (e.g., a paper cut), rapidly reproduce, and secrete a matrix of fibers that physically seal the wound. As other cell types (e.g., skin cells, muscle cells, nerves) regenerate, fibroblasts must be cleared away to allow space for them to grow. This process of rapid expansion followed by programmed senescence and clearance is necessary for quick healing without increasing cancer risk.[14]

Arresting growth of stressed, damaged cells

DNA damage and mitochondrial dysfunction are the primary drivers of cellular senescence due to aging. DNA damage includes single-stranded and double-stranded breaks, which can occur due to oxidative damage (e.g., high blood sugar, inflammation, pollution) or radiation (e.g., ultraviolet rays, x-rays, isotope radiation). DNA damage may also occur due to mutations (e.g., single-base deletions, additions, or substitutions) that impair the integrity of the genome. Once the DNA within a cell becomes damaged, any daughter cells produced by the damaged cell are at risk of accumulating the same DNA defects. By directing cells with DNA damage to arrest growth and reproduction before mutations can spread, senescence protects the body from diseases such as cancer, which can occur when a population of dysfunctional cells reaches a threshold within an organ or tissue.[15] Previous research has demonstrated that activation of pro-cancer genes within a cell induces senescence as a protective mechanism.[16]

Mitochondria, the major energy-producing organelles of most cells, contain their own genome separate from the DNA found in the nucleus. This mitochondrial DNA is inherited from mother to child and originates in the oocyte (i.e., egg cell) prior to fertilization. Because mitochondria must also maintain a functional genome, they are also susceptible to damage from oxidative stress and radiation. Oxidative stress is exceptionally high in mitochondria because free radical production is a necessary step of adenine triphosphate (ATP) synthesis, which occurs in the inner mitochondrial membrane.

Mitochondria with DNA damage or dysfunctional components can be transferred from a parent cell to a daughter cell, risking the spread of damage.[13] Cells that become senescent due to mitochondrial dysfunction, a hallmark of aging, are categorized by the mitochondrial dysfunction-associated senescence (MiDAS) phenotype, which is associated with the excessive release of inflammatory cytokines. The resulting inflammation damages healthy cells via oxidative damage and directs their behavior, a type of intercell communication called a paracrine effect. [17] [18]

Summaries

Below is a selection of summaries from current research investigating the role of senescence in health and disease.

Maternal diabetes causes birth defects by increasing cellular aging in mice.

Neural tube defects (e.g., spina bifida, hydranencephaly) are a group of congenital disabilities caused by incomplete development of the outer layers of the brain or spinal cord. Folate supplementation during pregnancy prevents an estimated 70 percent of neural tube defects, but additional therapies are needed. The following report explores the relationship between maternal diabetes and abnormal cell aging in the fetal nervous system in mice.

Previous research has demonstrated a relationship between maternal diabetes and the incidence of neural tube defects in mice; however, the mechanisms by which high maternal blood sugar levels interfere with fetal development are unknown. High levels of glucose cause oxidative damage and promote cellular senescence, a state in which cells are metabolically active but do not reproduce.

Aging cells accumulate damage over time and become senescent. In adults, an excess of senescent cells can promote inflammation and disease. In the developing fetus, senescence is vital for tissue remodeling and the development of limbs and organs. However, inappropriate senescence may lead to abnormal growth.

The investigators used multiple mouse models in their study in order to compare various biological variables. In a first experiment, they used a strain of mice that develop diabetes and compared them to wild-type mice, which are not predisposed to any disease. They injected pregnant females from both groups with rapamycin, a compound that slows cellular aging by inhibiting the enzyme mTOR, or a placebo. In a second experiment, they used a strain of knockout mice whose genomes do not contain the gene FoxO3a, a regulator of aging that may slow cellular senescence.

Maternal diabetes increased the abundance of biomarkers of cellular senescence and DNA damage in the lining of the brain in offspring. Pregnant diabetic mice that were exposed to rapamycin had offspring with lower levels of senescence biomarkers and fewer neural tube defects compared to the placebo. Offspring from FoxO3a knockout mice and mice with the non-functional FoxO3a gene experienced the same decrease in senescence biomarkers and neural tube defect rates as rapamycin-treated mice.

These results elucidate the mechanisms by which maternal diabetes can cause congenital disabilities through metabolic changes that accelerate aging.

Fasting or beta-hydroxybutyrate administration reduces the production of senescent cells.

Ketogenic diets, fasting, and exercise have all demonstrated the ability to extend healthspan and lifespan, possibly through mechanisms mediated by beta-hydroxybutyrate (BHB). However, the precise effects of BHB on the cellular mechanisms of aging are not well understood. Findings of one report show that BHB administration and fasting both reduce senescence in mice.

The researchers conducted an experiment that involved culturing human vascular endothelial (i.e., blood vessel cells) from umbilical cords and aortas, followed by an experiment with mice. To compare the effects of BHB supplementation and fasting, the researchers fed one group of mice a normal diet, then randomly assigned them to receive an injection of BHB or a placebo after they had fasted for just five hours. Using a second group of mice, the researchers randomly assigned half of the group to fast for 72 hours and the other half to eat normally. In both the cell culture and mice experiments, the researchers measured changes in gene expression and metabolic activity.

The researchers found that BHB reduced senescence in vascular cells due to increased expression of the transcription factor Oct4, which is a protein that binds to DNA and regulates cell regeneration and stem cell differentiation. Compared to mice that received a placebo injection, mice who received BHB had reduced senescence in vascular cells through the same Oct4 pathway as in cell culture. Mice that fasted also robustly activated Oct4, leading to activation of senescence-associated markers such as mTOR inhibition and AMPK activation, two pathways that modulate lifespan.

Prior to this study, it was not known whether Oct4 was active in adult cells; however, these results show fasting or BHB administration activates youth-associated DNA factors that reduce senescence in mice and cell culture. Future studies are needed to translate these results into relevant use for humans because humans have very different nutritional needs than mice and cells in culture.

Hyperbaric oxygen trial discovered a lengthening of up to 38% of the telomeres, decrease of up to 37% in senescent cells in certain cell populations.

With age, tissues lose their ability to function properly, leading to an increased risk of cancer, cardiovascular disease, Alzheimer's disease, and other chronic diseases. Cells become exhausted from replication over time and enter a state of senescence, meaning they will no longer reproduce because they are damaged. Findings of a new report demonstrate that hyperbaric treatments reduce the number of senescent immune cells.

Hyperbaric (i.e., high air pressure) treatments use increased atmospheric pressure and oxygen content to enhance the total amount of oxygen dissolved in the body, accelerating wound healing. Some forms of routine hyperbaric therapy cause the body to react as if it were experiencing hypoxia (i.e., low blood oxygen), a phenomenon called the hyperoxic-hypoxic paradox. Although some of the hypoxia-associated effects of hyperbaric treatments, such as sirtuin activation, stem cell proliferation, mitochondrial biogenesis, and neurogenesis, are associated with longevity, the effects of hyperbaric therapy on cellular senescence are unknown.

The authors recruited 35 participants aged 60 and older who did not have cognitive decline and lived independently. Participants completed 60 hyperbaric treatments distributed as five sessions per week for three months. Each session consisted of 90 minutes of breathing 100 percent oxygen at a pressure twice that of normal barometric pressure. The researchers collected blood samples at multiple time points to measure markers of senescence in peripheral blood mononuclear cells (PBMCs), which include T cell, B cells, monocytes, and natural killer cells.

By the 30th hyperbaric treatment, participants experienced statistically significant increases in telomere length, a marker of reduced senescence rate, in T-helper cells, B cells, and natural killer cells. Following all 60 treatments, telomere length increased by 30 percent in T-helper cells, 38 percent in B cells, and 22 percent in natural killer cells. Demonstrating further benefit, hyperbaric treatment reduced the number of senescent T-helper cells by 12 percent and cytotoxic T cells by 11 percent after 60 sessions.

These results show, for the first time in humans, that routine hyperbaric treatment reduced the rate of aging in immune cells. However, because this study utilized a small sample, reported large variations in the data, and did not contain a control group, these results must be replicated with future research before they can be fully interpreted.

Frequently Asked Questions

Q: What are the potential drawbacks to senolytic drugs as an aging therapeutic?

A: While senolytic drugs hold great antiaging potential, research regarding the safety of these drugs is scarce because the field is so young. As mentioned above in the Mechanisms of senescence section, senescence is a normal and necessary part of wound-healing, therefore misuse of senolytic drugs may have the unintended consequence of slowing the wound healing process or potentiating some types of cancer. However, further research is needed to understand the optimal use of senolytic drugs to maximize acute health and extend lifespan.

  1. ^ Cellular senescence in development, regeneration and disease Development 146, no. 20 (October 2019). https://doi.org/10.1242/dev.151837.
  2. ^ Senescence in Health and Disease Cell 169, no. 6 (June 2017): 1000–1011. https://doi.org/10.1016/j.cell.2017.05.015.
  3. ^ Ageing, Cellular Senescence and Neurodegenerative Disease International Journal of Molecular Sciences 19, no. 10 (September 2018): 2937. https://doi.org/10.3390/ijms19102937.
  4. ^ Hyperglycemia Accelerated Endothelial Progenitor Cell Senescence via the Activation of p38 Mitogen-Activated Protein Kinase Circulation Journal 70, no. 8 (2006): 1076–81. https://doi.org/10.1253/circj.70.1076.
  5. ^ Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue Diabetes 65, no. 6 (March 2016): 1606–15. https://doi.org/10.2337/db15-0291.
  6. ^ Telomere length as a marker of sleep loss and sleep disturbances: a potential link between sleep and cellular senescence Sleep Medicine 16, no. 5 (May 2015): 559–63. https://doi.org/10.1016/j.sleep.2015.02.519.
  7. ^ Social stress shortens lifespan in mice Aging Cell 17, no. 4 (May 2018): e12778. https://doi.org/10.1111/acel.12778.
  8. ^ Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease EBioMedicine 47 (September 2019): 446–56. https://doi.org/10.1016/j.ebiom.2019.08.069.
  9. ^ Fisetin is a senotherapeutic that extends health and lifespan EBioMedicine 36 (October 2018): 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015.
  10. ^ Spermidine attenuates bleomycin-induced lung fibrosis by inducing autophagy and inhibiting endoplasmic reticulum stress (ERS)-induced cell death in mice Experimental & Molecular Medicine 52, no. 12 (December 2020): 2034–45. https://doi.org/10.1038/s12276-020-00545-z.
  11. ^ Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis Aging 12, no. 13 (July 2020): 12750–70. https://doi.org/10.18632/aging.103177.
  12. ^ Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage BMC Complementary Medicine and Therapies 21, no. 1 (July 2021). https://doi.org/10.1186/s12906-021-03369-0.
  13. ^ a   b Mitochondrial Dysfunction Meets Senescence Trends in Biochemical Sciences 41, no. 3 (March 2016): 207–9. https://doi.org/10.1016/j.tibs.2016.01.005.
  14. ^ a   b   c Replicative senescence: a critical review Mechanisms of Ageing and Development 125, no. 10-11 (October 2004): 827–48. https://doi.org/10.1016/j.mad.2004.07.010.
  15. ^ Four faces of cellular senescence Journal of Cell Biology 192, no. 4 (February 2011): 547–56. https://doi.org/10.1083/jcb.201009094.
  16. ^ From Ancient Pathways to Aging Cells Connecting Metabolism and Cellular Senescence Cell Metabolism 23, no. 6 (June 2016): 1013–21. https://doi.org/10.1016/j.cmet.2016.05.010.
  17. ^ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype Cell Metabolism 23, no. 2 (February 2016): 303–14. https://doi.org/10.1016/j.cmet.2015.11.011.
  18. ^ Paracrine roles of cellular senescence in promoting tumourigenesis British Journal of Cancer 118, no. 10 (April 2018): 1283–88. https://doi.org/10.1038/s41416-018-0066-1.

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