Over time, an organism’s vital physiological functions deteriorate due to aging. Eventually, aging leads to cell death.
The causes of aging
Three major traits characterise aging:
- Primary drivers that cause damage
- Antagonistic drivers that react in response to the damage
- Integrative drivers that are a result of the damage accumulated over the cell’s existence
Telomere damage, epigenetic malfunction, mitochondrial dysfunction and DNA damage are primary drivers. On the other hand, an example of antagonistic class of drivers is senescence, while the integrative class consists of proteostasis dysfunction and disruptions in the signaling pathways.
Senescence is the state of stable, permanent cell growth deceleration. This process is connected to aging and age-related diseases. Besides changing an organism’s phenotype, senescence also causes chromatin, metabolism, autophagy changes and numerous proinflammatory factors to be released.
What is cellular senescence?
Unlike most cells, senescent cells don’t die off when they should, even after they stop multiplying. Instead, they remain and release chemicals that can cause inflammation.
A few senescent cells can remain and spread inflammation that can damage neighbouring cells, just like a mouldy piece of fruit corrupts the entire bowl [1]. There are, however, only a few senescent cells that are promising. Senescent cells express molecules, and compounds called senescent secretomes that play an essential role in embryonic development, childbirth, and wound healing.
Types of senescence
Senescence materialises in three different scenarios:
- Senescence due to regular aging
- Senescence due to age-related conditions
- Senescence induced in response to therapy (for example, chemotherapy)
Senescence due to normal aging: senescence resulting from natural aging has been studied extensively. Transgenic mice and senescence-prone progeroid mice are two efficient animal models used in these studies.
Researchers working on budding uninhibited by benzimidazole-related 1 (BubR1)-hypomorphic progeroid mice have found that some kinds of cells are more susceptible to damage from senescence. Sarcopenia occurs when adipose tissue mass is lost and muscle and fat progenitor cells undergo senescence. Additionally, as a result of cell-automated senescence, stem cells become less able to regenerate tissue
Senescence due to age-related diseases: Senescence often sets in when the body is weakened by a pathological illness. Many age-related diseases, including osteoarthritis, glaucoma, diabetes and cancer, are influenced by senescence. Several tumor suppressors, including p16INK4 and ARF, induce senescence as well.
Therapy-induced senescence: This type of senescence is seen as a result of treating children with cancer that involves bone marrow transplantation and organ transplantation. Medications may promote senescence-rich cells in blood cancers, which impair hematopoietic function and speed up tissue aging. Symptoms include premature aging, cognitive impairment and even heart disease.
We can gain a better grasp of the mechanisms and relationship between senescence and age-related decline in physiological functions by using powerful pharmacological and genetic tools. This understanding will aid in developing new therapeutic strategies to treat specific diseases and improve the overall health span of the aging population
How cellular senescence affects the body
With age, a person’s body produces more senescent cells. Age-related immune system declines leads to an accumulation of senescent cells, which taint healthy cells. It can affect a person’s ability to cope with stress, recover from injuries and learn new things because senescent cells in the brain can cause cognitive decline.
As a result, cellular senescence has been linked to cancer, diabetes, osteoporosis, cardiovascular disease, stroke, Alzheimer’s disease and osteoarthritis. Additionally, it has been associated with declines in eyesight, mobility and cognitive abilities. Researchers are investigating whether senescent skin cells may make a contribution to sagging and wrinkles, and if senescent cells can also trigger the cytokine storm of inflammation that causes COVID-19 to be so deadly [2].
A scientific fascination
Cellular senescence has been on scientists’ agendas since the early 1960s when Leonard Hayflick, PhD, and his colleague Paul Moorhead, PhD, disproved the long-held scientific belief that human cell samples could reproduce endlessly in lab cultures. According to Hayflick and Moorhead, cells enter senescence after a certain number of division cycles [3].
After that discovery, senescence was considered just an odd side effect of laboratory cell culture. Only a few research teams have studied it, but interest in it has soared in the past 20 years. It is currently a young but promising scientific discipline that has spurred NIH (National Institutes of Health) research and private industry funding for studies to discover and develop drugs that might help Mother Nature eliminate senescent cells.
The quest to extend life expectancy
Meanwhile, Jim Kirkland, MD, PhD, of the Mayo Clinic, and his former colleague Jan van Deursen, PhD, were forerunners of the senescence renaissance [4]. Kirkland has researched ways to remove senescent cells for nearly two decades.
Kirkland, a clinical geriatrician, says he was tired of prescribing the latest wheelchairs, walkers and incontinence products. Instead, he wanted to know if it was possible to slow down or reverse the fundamental aging processes in humans that lead to common health problems.
Kirkland and his team are currently concentrating on a combination of two drugs: dasatinib (D), a drug commonly used in leukemia chemotherapy; and quercetin (Q), an anti-inflammatory pigment found in grapes,onions, strawberries, tomatoes, red wine, and other fruits and vegetables. D&Q function as senolytics, which remove senescent cells when combined.
A very small pilot study was performed by Kirkland and colleagues in 2019 on 14 volunteers with idiopathic pulmonary fibrosis (IPF), a fatal, difficult-to-treat disease of the lungs [5]. According to the results, D&Q could be tested in larger controlled trials if the senolytic combination improved physical function in participants.
D&Q also cleared senescent cells in diabetic kidney patients in subsequent small clinical trials [6]. A mouse model of IPF showed that D&Q reduced inflammation, cleared senescent lung cells, and extended health span, but not longevity. Other age-related conditions like osteoporosis, glaucoma, macular degeneration, diabetic neuropathy and glaucoma are also being investigated with senolytics.
A study by Kirkland’s lab showed that senolytics delayed the onset of several age-related ailments in middle-aged mice. D&Q-treated mice were faster, stronger, and spryer than control mice, and their positive effects lasted until their final months [7]. Other studies showed that mice given D&Q had a 36 per cent longer average lifespan than mice not given D&Q [8].
By injecting healthy young or middle-aged mice with senescent cells tailored to their needs, Kirkland’s team tested the opposite approach. Mobility, speed, strength and frailty rates rapidly declined following this intervention. Furthermore, these negative effects persisted long after the transplanted senescent cells died.
The road to safe human use is still long
Kirkland emphasises the huge gap between mice and humans despite these studies posing exciting scientific and medical questions. Because senolytics and similar supplements or drugs are not proven safe outside of clinical trials, he frequently advises people not to take them.
Kirkland, his Mayo colleague Tamar Tchkonia, PhD; and Stefan Tullius, MD, PhD, of Harvard University Medical School, are also investigating other possible benefits of taming senescence to revitalise older tissues. Researchers are exploring whether treating livers or kidneys from older organ donors with senolytics previous to transplant could help restore damage that accumulates over time [9].
This could increase the viability and safety of older organs for transplantation, and reduce waitlists if true. As Kirkland explained, the field is ripe for future research due to the connections between senescence and age-related conditions.
[1] https://www.news-medical.net/life-sciences/Senescence-and-Aging.aspx
[2] https://pubmed.ncbi.nlm.nih.gov/32612617/
[3] https://pubmed.ncbi.nlm.nih.gov/13905658/
[4] https://pubmed.ncbi.nlm.nih.gov/22048312/
[5] https://pubmed.ncbi.nlm.nih.gov/30616998/
[6] https://pubmed.ncbi.nlm.nih.gov/31542391/
[7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078/
[8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082705/
[9] https://pubmed.ncbi.nlm.nih.gov/32855397/
