Aging is a systemic and multifaceted process with many root causes. In fact, there are twelve hallmarks of aging that contribute to all aspects of human aging–from fine lines on our face to age-related diseases like Alzheimer’s and arthritis. But recent breakthroughs in longevity science have revealed that not all twelve hallmarks of aging are equal. Some hold greater importance–and therefore greater potential as therapeutic targets in the aging process.
One mechanism of aging, cellular senescence, has been identified by longevity scientists as central to the other eleven hallmarks of aging. By targeting cellular senescence, scientists hope to unravel the interconnected web of aging factors by developing breakthrough therapies that could help people live longer lives in good health. Let’s take a closer look at why cellular senescence is central to aging and how targeted therapies can effectively reverse this process in the skin and our bodies as a whole.
01
What is cellular senescence?
In the 1960s, Leonard Hayflick determined that cells can only replicate and divide about 50 times before they cease to function due to the gradual accumulation of damage. [1] This normal aging process, called cellular senescence, is biologically intended to promote tissue homeostasis and prevent the proliferation of damaged cells that could potentially lead to tumors. When we’re young and healthy, our immune systems efficiently eliminate senescent cells as they arise, but this process becomes less efficient as we age. Plus, throughout our lives, we continuously encounter factors that induce premature senescence, such as oxidative stress [2], inactivation of tumor suppressor genes [3], and infections [4]. This results in an increasing accumulation of senescent cells in our bodily tissues. Like rotten apples that spoil the bunch, these cells drive neighboring cells into senescence by releasing pro-aging and inflammatory signals. This process significantly accelerates aging and age-related diseases. Read more on cellular senescence here.
02
How is cellular senescence related to the other eleven hallmarks of aging?
Before we dive into the science, here’s a quick look at the twelve hallmarks of aging:(Note: Hallmarks 1-9 have been established since 2013, and 10-12 were recently added in 2023)
- Genomic instability
- Telomere attrition
- Epigenetic alterations
- Loss of proteostasis
- Deregulated nutrient sensing
- Mitochondrial dysfunction
- Cellular senescence
- Stem cell exhaustion
- Altered intercellular communication
- Chronic inflammation
- Disabled macroautophagy
- Dysbiosis
Cellular senescence is arguably the most detrimental of these twelve biological phenomena and the one that links them all together. Senescence can be caused by five of the twelve hallmarks that are primary factors of cell aging: 1) genomic instability, 2) telomere attrition, 3) epigenetic alterations, 6) mitochondrial dysfunction, and 11) disabled macroautophagy. These factors can all be induced by both internal triggers and environmental factors like UV rays, environmental toxins, and daily stress.[5] As senescent cells accumulate in tissues across the body, they drive further aging by triggering the remaining six hallmarks of aging: 9) altered intercellular communication, 5) disruption of nutrient signaling, 4) irregular protein manufacturing, 8) exhaustion of replacement stem cells, 10) chronic inflammation, and 12) dysbiosis.[6] Because senescence is directly related to all other hallmarks, it is considered a “central pillar” of aging.
Telomere damage, epigenetic dysregulation, DNA damage, mitochondrial dysfunction, and disabled macroautophagy are primary drivers of damage in aging. Several of these drivers of damage can induce senescence. Senescence can in turn drive the consequential aging hallmarks in response to damage: stem cell exhaustion and altered intercellular communication. Other responses to damage, such as proteostatic dysfunction, chronic inflammation, dysbiosis, and nutrient signaling disruption, are also integrally linked with senescence response. [6]
03
Why is cellular senescence a prime target for longevity therapeutics?
Because cellular senescence is so central to other aging processes, preventing and reversing cellular senescence is a very effective method for extending healthspan–from skin health to whole-body wellbeing. Senescent cells in the skin can contribute to wrinkles, crepiness, and disease progression [7] while senescent cell accumulation in other tissues can contribute to diseases such as osteoarthritis [8] and type 2 diabetes [9]. Due to its role in the etiology of many age-related diseases, preventing and disrupting senescence can effectively delay aging, making it a prime target for longevity therapeutics.
04
What are senotherapeutics and how do they target cellular senescence?
Senotherapeutics are a class of molecules that have been shown to prevent the accumulation and/or enhance the removal of senescent cells. Data from animal and clinical models suggest that senotherapeutic drugs and peptide therapies can effectively target and reverse cellular senescence in two ways:[10]
- Senolytics: enhance the specific killing of senescent cells. For a senolytic to be safe it should target senescent cells without affecting the viability of neighboring healthy cells.
- Senomorphics: change senescence phenotypes by enhancing the cell function or inhibiting the harmful signals secreted by senescent cells that drive neighboring cells into senescence (also calledsenescence-associated secretory phenotype or SASP).
05
What is the potential for senotherapeutics in the longevity field?
Along with longevity-focused lifestyle habits like good nutrition and regular exercise, the use of senotherapeutics may one day be a powerful tool for preventing age-related diseases and reversing aging. Nearly 30 clinical trials are currently investigating the role of senotherapeutics in treating various cancers, aging phenotypes, neurodegenerative diseases, and infections. [11]When it comes to skin longevity, the future is already here. The researchers at OneSkin examined nearly one thousand potential senotherapeutic peptides in the laboratory to discover one lead peptid eand further optimize it to become OS-01: the first peptide proven to reduce skin’s biological age. [12] Lab studies on human skin samples and cells have shown that the OS-01 peptide reduces the number of senescent cells in the skin by up to 50%.[12] These results show that by reducing cellular senescence, the OS-01 peptide can slow the aging process and associated aging processes, ensuring that skin behaves, appears, and feels like younger skin for longer. [12]
Key Takeaways:
- Cellular senescence is at the center of all other hallmarks of aging and can mediate many aging phenotypes.
- Targeting cellular senescence effectively inhibits all other hallmarks of aging, such as altered cellular communication, cellular dysfunction, and irreversible cellular damage.
- Therapeutic interventions against cellular senescence can significantly reduce symptoms of aging, as senescence-mediated aging is a leading indicator of many diseases.
- Senotherapeutics can effectively target aging at the cellular level to prevent age-related diseases and extend healthspan - the ultimate goal of longevity science.
References
- https://www.thelancet.com/article/S0140-6736(11)60908-2/fulltext
- http://www.ncbi.nlm.nih.gov/pubmed/29747066
- https://pubmed.ncbi.nlm.nih.gov/17136094/
- https://pubmed.ncbi.nlm.nih.gov/34103349/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344376/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748990/
- https://pubmed.ncbi.nlm.nih.gov/26286607/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785239/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546206/
- https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(21)00300-7/fulltext
- https://www.jci.org/articles/view/158450#SEC3
- https://www.nature.com/articles/s41514-023-00109-1
