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. 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. 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 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.”

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.
This small study represents a major paradigm shift in treatment strategy.

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.

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.”

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, p16 Ink4a + and SA-βgal, cell abundance in mice.  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. 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.

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. There are many ways to optimize immune function starting with diet
and lifestyle and adding nutraceuticals, botanical medicine, and peptide therapies.

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 study. EBioMedicine, 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

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