Skin Deep on Senescence

With old age comes wisdom, but it also comes with frailty, reduced mobility, and cognitive decline. It’s no wonder, then, that the quest for the “fountain of youth” has captivated societies for millennia. From myths of ancient artifacts promising immortality to dubious elixers like snake oil, humans have long been fascinated by the concept of slowing down or controlling the aging process.

In our pursuit to understand the intricacies of aging, the spotlight turns to cellular senescence. Cellular senescence is a bit like cell limbo, yet it has substantial implications for tissue decline during the aging process. Senescent cells are present throughout life, critical for proper development and wound healing (1). However, once they accumulate in excess — as during aging — they compromise their biological environment(s) for age-dependent deterioration.

So, what happens at the cellular level as we age? What role do senescent cells play in the aging process? In this article, we’ll delve into the complexities of cellular senescence, exploring its implications on age-related tissue decline. We’ll also explore promising methods of addressing cellular senescence to slow down or even reverse aging — no snake oil required.

What Is Cellular Senescence?

Cellular senescence is the term given to cells that have devolved into an irreversible cell cycle arrest as a response to various stressors. These stressors include but are not limited to: 

• DNA damage
• Replicative stress/telomere shortening
• Oxidative stress
• Mitochondrial dysfunction
• Radiation
• Oncogene induction (2)

Many of these stressors are also hallmarks of aging.

Indeed, cellular senescence itself can bes a hallmark of aging, tightly correlated to chronic disease and aging as a consequence (3, 4). Research shows that senescent cell accumulation may contribute to tissue dysfunction and subsequent aging.

Senescent cells are also resistant to cell death, making their comparison to zombies entirely appropriate. And, similar to a zombie-like situation, senescent cells influence neighboring cells to convert one into many!

In turn, senescent cells wreak havoc on their environment of healthy neighboring cells through a cascade of secreted chemicals called the senescence-associated secretory phenotype (SASP). This collection of cytokines, chemokines, growth factors, and proinflammatory factors degrade tissue integrity and are associated with aging (5). The SASP is another way senescent cells are akin to zombie cells!

Senescent Cell Detection

Numerous efforts have been made to optimize senescent cell clearance in order to extend health span and, in turn, lifespan. Yet one huge bottleneck in cellular senescence research is that there is no consensus on a universal marker to identify senescent cells. Several biomarkers exist to detect common hallmarks of senescence, but even so, cellular senescence exists in a spectrum.

The cell cycle arrest marker p16, for one, is widely used for detecting senescent cells (6). This biomarker reliably (but partially) labels senescent cells, which can then be promptly targeted for elimination. A groundbreaking paper used this labeling method to detect and eliminate p16-positive cells throughout the body in mice (7). By eliminating these particular senescent cells, researchers were able to extend lifespan and healthspan in the mice models, thus emphasizing the implications of senescent cells for longevity. 

Previously, this detection method and then p16-positive senescent cell clearance extended lifespan and health span to physiologically average levels in mice (7), also demonstrating the impact of senescent cells on longevity. On the other hand, p16 has also been used to identify resident senescent cells deemed “sentinels” necessary for organ repair and function (8). Thus, the (re)search for selectively yet effectively targeting which p16 cells become modulated via small molecules requires further consideration. 

How Is Senescence Related to Skin Aging?

The skin is one of the most active tissues in the human body concerning regeneration. However, a limited number of cell divisions can occur to maintain the barrier function of the organ. Once that limit is reached, one popular theory is that cells enter the limbo that is senescence — cell cycle arrest. 

Another outstanding theory of cellular senescence is that these abnormal cells accumulate in tissues (like skin [9]), disrupting homeostatic processes and contributing to aging. Skin-specific senescence also impacts whole-body aging due to the spread of senescent cell influence (secretome, or SASP) to healthy neighboring cells, termed paracrine senescence (10). Cellular senescence can arise from intrinsic and extrinsic factors, typically induced by cellular damage (11). 

Three different therapeutic strategies exist for the removal of senescent cells to delay aging in various organs, including skin: 1) Selective induction of cell death, 2) Inhibition of SASP, and 3) Optimized immune response (12).

Oxidative stress (specifically mtROS, mitochondrial ROS) also drives cellular senescence. Senescent cells accumulate in aging human and mouse skin (13, 14). Cellular senescence also occurs when antioxidant defenses are compromised in the skin (15), leading to genomic damage. Further, epidermal aging phenotypes such as skin thinning and stem cell differentiation occur. Combined, one can infer that oxidative stress is one cause and consequence of cell senescence in skin aging.
Genomic stability and accurate DNA repair is critical for senescence prevention in skin. Deletion of Mdm2 (the main regulator of p53 tumor suppressor, involved in many cancers) caused several aspects of skin senescence, including disrupted epidermal stem cell function and also induced accelerated aging phenotypes like hair loss, reduced wound healing, and epidermal thinning in mouse skin (16). This is but another instance where hallmarks of aging are heavily implicated in skin organ homeostasis and aging.

Breaking News: Senolytics in Skincare?!

Within the skincare realm, a revolutionary development is causing ripples across the beauty industry — the emergence of senolytics.These are a group of molecules that eliminate senescent cells, while their molecular counterparts, senomorphics, interfere with the SASP signature of senescent stem cells. The potential of these interventions is not confined to theoretical speculation; compounds like metformin and rapamycin have been tested topically with promising anti-aging effects (24, 25).

A Closer Look at Skin Biology

Widespread cellular senescence in skin has profound effects on dermatological pathophysiology, warranting study for cutting-edge therapeutics to prevent skin aging. Natural product-derived compounds, such as polyphenols and flavonoids, are a growing body of promising small molecules used to control the development of senescent cells in skin (17). Their mechanisms often involve modulation of anti-inflammatory pathways or collaboration with antioxidant enzymes, curbing the immune response of the SASP or reducing oxidative stress and damage (18). 

Fisetin’s Role

An August 2023 study demonstrated that fisetin acts on the dermis component of human skin (19). Fisetin treatment increased collagen levels and reduced senescent cell signals (SASP), improving skin aging. Importantly, no other adverse effects were observed. Could fisetin be the next big thing in skincare, promising a paradigm shift in our approach to anti-aging regimens?

NOVOS Core Battles Senescent cells, Including in Skin

Fisetin isn’t the only promising compound in the pursuit for longevity. NOVOS Core is on the leading edge of longevity research, with products like NOVOS Core designed to target the root causes of aging. 

NOVOS Core is composed of ingredients that prevent the development of senescent cells. In fact, NOVOS Core as a whole has been shown to protect against DNA damage and senescence, with longevity-promoting ingredients that include:

• Fisetin: Fisetin is an all-around rockstar molecule and is abundant in fruits and vegetables such as grapes, strawberries, apples, persimmons, onions, and cucumbers. It can work as a single senolytic (not like in a combination) for senescent cell clearance and even rivals the popular senolytic duo of dasatinib and quercetin (D+Q) (20).
• Magnesium: This exceptional mineral salt is necessary for mitochondrial and antioxidant function, and chronic deficiencies induce senescence, thus playing a role as a senolytic element (21).
• Lithium: Novel data using microdosed lithium on human astrocytes showed a senomorphic, neuroprotective effect and prevented inflammatory SASP responses (22).
• Ginger: Compounds in ginger were recently identified as novel senolytics, outperforming the usual favorite combination of D+Q (23).

Ageless Beauty Starts From Within

Cellular senescence is a complex yet intriguing field for anti-aging studies and therapeutic interventions. Examining the intricacies of cellular senescence offers a deeper understanding of the aging process and paves the way for groundbreaking interventions. We’re at the cusp of a new era in skincare and anti-aging, armed with insights into senolytics, senomorphics, and innovative formulations like NOVOS Core.

Backed by extensive research, NOVOS Core presents a holistic approach to counteracting senescence, targeting both whole-body and skin aging. With an array of ingredients carefully selected for their contributions to healthy aging and longevity, NOVOS Core exemplifies the progress being made in anti-aging science.

References

1. https://pubmed.ncbi.nlm.nih.gov/31575608/
2. https://pubmed.ncbi.nlm.nih.gov/33328614/
3. https://pubmed.ncbi.nlm.nih.gov/23746838/
4. https://pubmed.ncbi.nlm.nih.gov/36599349/
5. https://pubmed.ncbi.nlm.nih.gov/20078217/
6. https://pubmed.ncbi.nlm.nih.gov/30190724/
7. https://pubmed.ncbi.nlm.nih.gov/26840489/
8. https://pubmed.ncbi.nlm.nih.gov/36227993/
9. https://pubmed.ncbi.nlm.nih.gov/9732048/
10. https://pubmed.ncbi.nlm.nih.gov/35012887/
11. https://pubmed.ncbi.nlm.nih.gov/25855157/
12. https://pubmed.ncbi.nlm.nih.gov/27031122/
13. https://pubmed.ncbi.nlm.nih.gov/756813
14. https://pubmed.ncbi.nlm.nih.gov/19627270
15. https://pubmed.ncbi.nlm.nih.gov/22278880/
16. https://pubmed.ncbi.nlm.nih.gov/21334322/
17. https://pubmed.ncbi.nlm.nih.gov/36830002/
18. https://pubmed.ncbi.nlm.nih.gov/34201952/
19. https://pubmed.ncbi.nlm.nih.gov/37736858/
20. https://pubmed.ncbi.nlm.nih.gov/30279143/
21. https://pubmed.ncbi.nlm.nih.gov/36555859/
22. https://pubmed.ncbi.nlm.nih.gov/32534451/
23. https://pubmed.ncbi.nlm.nih.gov/35349590/
24. https://pubmed.ncbi.nlm.nih.gov/31761958/
25. https://pubmed.ncbi.nlm.nih.gov/36715895/