Understanding Cellular Senescence and its Role in Wellness

The latest research in anti-aging and regenerative medicine has been focused on senescent cells and the role they play in the aging process, the body’s ability to heal, and chronic inflammatory disease. A senescent cell is one that undergoes changes in gene expression resulting in a loss of the ability to replicate, apoptosis or programmed cell death resistance and increased secretion of pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). 

Senescence is often induced by such stresses as DNA damage, telomere shortening, oncogenic mutations, metabolic and mitochondrial dysfunction, oxidative stress, and inflammation. (1) This process is common during aging and senescent cells not only increase in number as we age but due to their increased secretion of SASP they accumulate in areas of pathogenesis or injury perpetuating inflammatory and immune responses that can lead to and exacerbate conditions such as Alzheimer’s, dementia, Parkinson’s, osteoarthritis, autoimmune disease, metabolic syndrome, and essentially any chronic illness or inflammatory response.

Cellular senescence evolved as a protective mechanism during times of DNA damage, immune dysregulation, mitochondrial dysfunction, and oxidative stress that results from exposure to environmental toxins, inflammatory foods, sedentary lifestyles, chronic microbial infections, physical trauma, and chronic mental/emotional stress. Most of these stressors put cells at risk of developing cancer; thus, senescence-associated growth arrest serves as a potent tumor-suppressive mechanism. (7) Unfortunately, the pro-inflammatory secretions and signaling from senescent cells can lead to damage to surrounding healthy cells and tissue dysfunction perpetuating the inflammatory process. The senescence-linked secretory phenotype can also promote metabolic dysregulation, stem cell dysfunction, and loss of resilience (6) contributing to local and whole-body dysfunction that promotes tissue degeneration, chronic inflammation, and immune dysfunction.

If we want to promote optimal healing, delay the onset of aging-related disease and optimize the quality of life we have to remove the obstacle to cure, cellular senescence.

Research has been focusing on senolytic agents to kill and eliminate senescence cells. Promising research has been done using dasatinib a chemotherapy drug and quercetin to selectively trigger apoptosis or programmed cell death in senescence cell that is otherwise apoptosis-resistant. A study published in Nature Medicine by Xu and colleagues showed that the use of senolytic agents dasatinib plus quercetin alleviated physical dysfunction and increased late-life survival in aged mice. The drugs also alleviated and even prevented physical dysfunction in young mice who received senescent cell transplants. The study then tested dasatinib plus quercetin in vitro using human adipose tissue. Here Xu described his findings “We observed naturally occurring human senescent cells being cleared in these tissue samples by our senolytic drug cocktail. We also observed a reduction in the inflammatory cytokines in these tissues, while key adipokines were not affected. This demonstrates that these senolytic drugs can decrease inflammation without a global killing effect.” (1)

The University of Texas Health Science Center at San Antonio just completed the first-in-human pilot study using senolytic agents in 14 older adults diagnosed with stable, primarily mild-to-moderate idiopathic pulmonary fibrosis. Current drug therapies for this condition have not been effective and prognosis remains poor. Participants were given dasatinib and quercetin for a short duration and showed improvement in six-minute walk test, timed sitting-to-standing repetitions, and increased mobility gains. Pulmonary function test was not changed. 

“Here, we’ve therapeutically targeted a fundamental biological hallmark of aging that is implicated in IPF, and we show early but promising results for the first time in human patients. This small study represents a major paradigm shift in treatment strategy.” Jamie Justice, Ph.D., assistant professor at Wake Forest medical school, co-lead investigator and corresponding study author. (8) The use of senolytic agents is a promising treatment for age-related and inflammatory disease and further research should be encouraged. Treatments are often singular or intermittent minimizing adverse effects, however, the potential for side effects is not fully understood. Further studies will help the understanding of potential side effects, most effective dosing, optimal times for initiation of senolytic treatments for certain disorders, and determining conditions that can be treated by senolytics. (6)

The focus on senolytic agents is an exciting new frontier in medicine and one that could have vast implications on health. That being said we should not forget how effective diet and lifestyle have proven to be on health. Research has also shown how these foundations of health help both decrease and clear senescent cells.

The Importance of Diet and Lifestyle:

Diet and Exercise

A study published in the journal Diabetes by Schafer and colleagues evaluated the effects of diet and exercise on senescent cell markers in the adipose/fat tissue of mice.  Mice were either fed a normal PicoLab rodent diet or a high-fat diet enriched with saturated fat, cholesterol, and high fructose corn syrup mimicking a fast-food diet for 4 months. Mice fed a fast-food diet demonstrated significant increases in the expression of pro-inflammatory SASP markers compared to mice fed a normal diet. Interestingly in sedentary and exercised mice fed a normal diet, ∼2% of cells stained were positive for biomarkers of senescence cells in comparison, more than 12% of cells in sedentary mice fed the fast-food diet stained positively for senescence biomarkers. Strikingly, exercise nullified this effect of the fast-food diet, and as a result, the percentage of cells positive for senescence biomarkers in exercised fast food-fed mice were identical to that of normal diet-fed middle-aged mice. Schafter concluded “The current study demonstrates the robust effects of modifiable lifestyle factors on the accumulation of senescent cells and the expression of the SASP in middle age. Our data highlight the harmful consequences of nutrient excess and the remarkably protective influence of exercise on this biological process and, in turn, measures of physical, cardiovascular, and metabolic function. In the face of population aging, an obesity epidemic, and global reductions in physical activity, these findings have significant implications for human health.”(2)

Intermittent fasting

Intermittent fasting has shown vast health benefits including weight loss, decreased blood sugar levels, improved insulin sensitivity, prevention of neurodegenerative diseases, the reversal of aging processes, enhanced mental clarity and concentration, improved immune function and decreased inflammatory markers all of which correlate to a decrease in cellular senescence. One study showed that caloric restriction was associated with decreased senescent biomarker, p16Ink4a + and SA-βgal, cell abundance in mice. (9) Intermittent fasting also increases autophagy a process that cleans up cellular debris from damaged cell organelles, oxidative stress and misfolded proteins. Intermittent fasting benefits on health may be due both to decreasing senescent cells and also alleviating the affliction SASP have on the body.

Sleep

A study done at UCLA looked at the effects of partial sleep deprivation in older adult humans on DNA damage responses, senescence biomarkers p16 and senescence-associated secretory phenotype (SASP). One night of partial sleep loss in older adults induced gene expression changes consistent with an increase in the DNA damage response and the promotion of the senescent associated secretory phenotype. (10) Sleep is a foundation of health that plays a role in all inflammatory process and disease. Sleep is the time when our body regenerates and repairs and is a crucial part of the prevention and treatment in cellular senescence.

Meditation/Mindfulness/Biofeedback

Research has connected psychological stress with shorter telomere length and increased inflammatory markers regarding aging, but until Torvald and colleagues proposed the Neuro-Immuno-Senescence Integrative Model (NISIM) the specific pathways connecting psychological stress and cellular senescence was not well understood. NISIM suggest how heart rate variability (HRV), which is a well-established physiological marker for how well an individual’s nervous system adapts to acute and chronic stress is related to cellular senescence.  This model demonstrates how individuals with lower stress regulation capacity have increased production and release of cytokines and an increase in reactive oxygen species.  Increased reactive oxygen species due to reduced ability to regulate stress causes oxidative telomere damage resulting in cellular senescence. (14)

Utilizing meditation, mindfulness practices and heart rate variability training with biofeedback are all simple and effective ways to decrease inflammatory markers, lower cortisol levels (stress hormone), and lengthen telomeres all of which can contribute to fewer senescent cells. 

Optimizing Immune Function

The immune system is the first line of defense after injury or trauma.  How well our immune system is able to respond not only to injury or trauma but also environmental toxins such as pesticides, herbicides, plasticizers, heavy metals, and mycotoxins will directly affect the potency of senescent cells. Immune cells secrete cytokines or protein messengers that stimulate tissue rebuilding, including stem cell differentiation, improved circulation, resident tissue activation, and connective tissue synthesis. Whether initiated by trauma, infection, or toxin exposure the local tissue environment dictates immune responses. Thus, both the tissue-specific SASPs and the resulting tissue-specific immune response likely work together to define subsequent tissue repair or chronic disease pathogenesis. (10). There are many ways to optimize immune function starting with diet and lifestyle and adding nutraceuticals, botanical medicine, and peptide therapies. Detoxification to improve the body’s ability to eliminate environmental toxin exposures lessening the body’s burden is also a fundamental piece to improving immune function.

In summary, cellular senescence is the process in which cells stop functioning normally and begin to secrete inflammatory signals. The inflammation stimulated by senescent cells can lead to tissue dysfunction and even turn healthy cells into senescent cells leading to chronic inflammation, tissue degeneration, and chronic conditions such as neurodegenerative disease, osteoarthritis, and osteoporosis.

Some therapies to combat the progression of cellular senescence as discussed above are the use of senolytic agents (most well researched are dasatinib and quercetin). Also, studies have shown, and are continuing to show, that good diet and exercise are important, however, exercise can even mitigate the effects of a poor diet regarding cellular senescence. Adequate sleep, stress reduction and supporting a healthy immune system are all proving to be extremely important approaches for decreasing and eliminating senescent cells.

Reference:

  1. Xu, Ming et al. “Senolytics improve physical function and increase lifespan in old age.” Nature medicine vol. 24,8 (2018): 1246-1256. doi:10.1038/s41591-018-0092-9
  2. Schafer, Marissa J et al. “Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue.” Diabetes vol. 65,6 (2016): 1606-15. doi:10.2337/db15-0291
  3. Shetty, Ashok K et al. “Emerging Anti-Aging Strategies – Scientific Basis and Efficacy.” Aging and disease vol. 9,6 1165-1184. 4 Dec. 2018, doi:10.14336/AD.2018.1026
  4. Jeon, Ok Hee et al. “Senescent cells and osteoarthritis: a painful connection.” The Journal of clinical investigation vol. 128,4 (2018): 1229-1237. doi:10.1172/JCI95147
  5. Ok Hee Jeon et al. “Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment.” Nature Medicine Vol 23, pages775–781 (2017)
  6. Kirkland JL, Tchkonia T (2017). Cellular Senescence: A Translational Perspective. EBioMedicine, 21:21–28.
  7. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685–705. doi: 10.1146/annurev-physiol-030212-183653.
  8. Jamie N. Justice, Anoop M. Nambiar, Tamar Tchkonia, Nathan K. LeBrasseur, Rodolfo Pascual, Shahrukh K. Hashmi, Larissa Prata, Michal M. Masternak, Stephen B. Kritchevsky, Nicolas Musi, James L. Kirkland. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot studyEBioMedicine, 2019; DOI: 10.1016/j.ebiom.2018.12.052
  9. Krishnamurthy, Janakiraman et al. “Ink4a/Arf expression is a biomarker of aging.” The Journal of clinical investigation vol. 114,9 (2004): 1299-307. doi:10.1172/JCI22475
  10. Carroll, Judith E et al. “Partial sleep deprivation activates the DNA damage response (DDR) and the senescence-associated secretory phenotype (SASP) in aged adult humans.” Brain, behavior, and immunity vol. 51 (2016): 223-9. doi:10.1016/j.bbi.2015.08.024
  11. Matzinger P, Kamala T. Tissue-based class control: the other side of tolerance. Nat Rev Immunol. 2011;11(3):221–230. doi: 10.1038/nri2940
  12. Kurth, Florian et al. “Promising Links between Meditation and Reduced (Brain) Aging: An Attempt to Bridge Some Gaps between the Alleged Fountain of Youth and the Youth of the Field.” Frontiers in psychology vol. 8 860. 30 May. 2017, doi:10.3389/fpsyg.2017.00860
  13. Alda, Marta et al. “Zen meditation, Length of Telomeres, and the Role of Experiential Avoidance and Compassion.” Mindfulness vol. 7 (2016): 651-659. doi:10.1007/s12671-016-0500-5
  14. Ask, Torvald F., et al. “The Neuro-Immuno-Senescence Integrative Model (NISIM) on the Negative Association Between Parasympathetic Activity and Cellular Senescence.” Frontiers in Neuroscience, vol. 12, 2018, doi:10.3389/fnins.2018.00726.

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