Senescent cells accumulate in the skin with age and environmental stressors, playing a significant role in skin aging and dysfunction. Specifically, senescent melanocytes cease their normal function of dispersing melanin to surrounding keratinocytes, leading to  potential areas of hypopigmentation.

However, these senescent melanocytes also release a cocktail of pro-inflammatory cytokines, chemokines, and growth factors, collectively known as the Senescence-Associated Secretory Phenotype (SASP). This SASP acts as a local inflammatory trigger, paradoxically stimulating active melanocytes to produce excess pigment, contributing to inflammatory hyperpigmentation and conditions like melasma.

Senescent fibroblasts also contribute to this pro-inflammatory environment through their own SASP. The chronic inflammation from these senescent cells can elevate matrix metalloproteinase-1 (MMP-1) activity, which degrades collagen and elastin, ultimately leading to a weaker, thinner, and more disorganized dermal matrix.

Argireline Amplified Peptide while softening lines and wrinkles and found in SkinMed Hyal Serum is believed to help restrict cells from becoming senescent by modulating cellular stress responses and promoting a more youthful cellular environment.

While the exact mechanisms are still being fully elucidated, it is thought to influence pathways related to cellular longevity and resilience, potentially by improving protein homeostasis or reducing oxidative stress, thereby delaying the onset of senescence in skin cells like fibroblasts and melanocytes

Senotherapeutics are a class of compounds that target senescent cells, either by eliminating them (senolytics) or by modulating their harmful effects, particularly the Senescence-Associated Secretory Phenotype (SASP) (senomorphics).

While many senotherapeutics do possess antioxidant properties, their primary mechanism of action goes beyond simply neutralizing free radicals, directly addressing the root cause of cellular senescence.

There a number of prospective topical and oral agents classified as senotherapeutics/senolytics that offer more than just antioxidant benefits, with a focus on their impact on skin:

Topical Agents (Senolytics & Senomorphics for Skin):

• Topical compounds which targets anti-apoptotic cells and thereby induces senescent cell programmed death, also decreases inflammation, accelerates wound healing  and tsargets dysfunctional cells
• There are senomorphics which suppress the SASP (Senescence-Associated Secretory Phenotype) without necessarily killing senescent cells

• Another compound exhibits both

• A Senolytic effect: It’s claimed to induce apoptosis in senescent cells.
• A Senomorphic effect: It inhibits the secretion of SASP factors like interleukins (IL-6, IL-8) and collagenase (MMP-1), preventing the spread of senescence and restoring fibroblast function (this may be dangerous if senescence is a last resort pathway to prevent the cell becoming malignant).

• Some peptides are being investigated for their senotherapeutic properties, acting as senomorphics by reducing biological age markers in skin and improving skin health, potentially outperforming traditional anti-aging ingredients like retinol.
• Their mechanism often involves influencing cellular signalling pathways to promote youthful cell behaviour, rather than solely antioxidation.

• Natural Extracts/Botanicals with Senolytic/Senomorphic Properties (e.g., EGCG, Curcumin, Fisetin, Quercetin both topical but maybe better as a supplement

While these compounds are well-known antioxidants, their classification as senolytics or senomorphics highlights their ability to selectively eliminate senescent cells or modulate the SASP.

• Epigallocatechin Gallate (EGCG) from green tea: Shown to lower the number of senescent fibroblasts in skin and suppress SASP factors.

• Curcumin from turmeric: Exhibits senolytic activity and can enhance the efficacy of other senolytics.

• Fisetin (from apples, strawberries): Considered a potent senolytic, capable of reducing SASP factors and reversing senescence in fibroblasts.

• Quercetin (from various fruits and vegetables): While an antioxidant, it also acts as a senolytic, particularly in combination with other compounds, by targeting anti-apoptotic pathways in senescent cells.

Oral Agents (Senolytics & Senomorphics):

• A cancer drug combined with Quercetin (a flavonoid) work synergistically to selectively induce apoptosis in senescent cells by targeting anti-apoptotic pathways.

This combination has been shown to improve age-related conditions in animal models and is undergoing human clinical trials for various age-related diseases, including those with skin manifestations.

• Fisetin: As mentioned above, fisetin is a potent senolytic and can be taken orally. It’s more effective at reducing SASP factors and reversing senescence than some other natural compounds, and has shown promise in animal studies for anti-aging effects.

Metformin: Primarily an anti-diabetic drug, metformin is also considered a senomorphic due to its ability to inhibit pathways implicated in cellular senescence and SASP production. It has shown promise in extending lifespan in animal studies and is being investigated in human trials (TAME trial) for its anti-aging effects, including potential benefits for skin aging.

• EGCG: (Epigallocatechin gallate oral EGCG has demonstrated the ability to lower senescent fibroblasts and suppress senescence in various cell types, protecting skin and reducing inflammation.

• Olive Polyphenols: These collectively act as senolytic and senostatic (senomorphic) agents, capable of lowering SASP factors and reversing senescence in fibroblasts.

It’s important to note that while research on senotherapeutics is rapidly advancing, many of these agents are still in early stages of investigation, especially for their specific applications in human skin health. Always consult with a healthcare professional before incorporating new supplements or treatments.