Ingrediente Unico

What is cellular senescence?

Throughout the aging process, the skin is continuously exposed to internal and external factors that lead to cumulative damage, such as oxidative stress, ultraviolet radiation, and environmental pollution. In response to these stressors, cells activate different molecular response programs. One of these mechanisms is the permanent arrest of the cell cycle, known as cellular senescence.

Cellular senescence is a state in which the cell irreversibly stops dividing while remaining metabolically active. These are often referred to as “zombie” cells: they neither die nor are cleared, yet they no longer contribute to tissue regeneration and continue to secrete mediators that alter their microenvironment and impair the function of neighboring cells.

Senescent cells tend to accumulate progressively with age. When natural clearance mechanisms become insufficient, this accumulation disrupts skin regeneration, alters the activity of fibroblasts and keratinocytes, and contributes to the degradation of the extracellular matrix.

This process is influenced by multiple cellular mechanisms. Accumulated DNA damage, progressive telomere shortening, and sustained activation of inflammatory signaling promote the persistence of cells in a senescent state. Over time, these changes contribute to the structural and functional decline of the skin.

SASP: a key driver of skin aging

Senescent cells develop what is known as the senescence-associated secretory phenotype (SASP), a set of bioactive molecules that are continuously synthesized and released into the tissue microenvironment.

The SASP is composed of various mediators, including:

• Pro-inflammatory cytokines
• Chemokines
• Matrix metalloproteinases (MMPs)
• Dysregulated growth factors

The sustained release of these mediators generates a state of chronic low-grade inflammation, which disrupts skin homeostasis and amplifies the effects of cellular aging. This environment promotes the degradation of collagen and elastin, the disorganization of the extracellular matrix, the impairment of barrier function, and the induction of senescence in neighboring cells.

From an advanced dermocosmetic perspective, modulating the SASP is considered a key strategy to preserve structural integrity, maintain repair capacity, and support the homeostatic balance of the skin.

Strategies to target cellular senescence

Advances in the understanding of cellular senescence have enabled the identification of different strategies aimed at reducing its impact on the skin. Broadly, these can be divided into two main approaches: senolytic and senomorphic.

The senolytic approach aims to selectively eliminate senescent cells accumulated in the tissue. The controlled removal of these cells may reduce the chronic inflammation associated with the SASP and promote a more favorable environment for regeneration. However, this type of intervention involves complex challenges related to safety, cellular selectivity, and regulatory considerations, and is therefore more advanced in medical research than in dermocosmetic applications.

By contrast, the senomorphic approach seeks to modulate the biological behavior of senescent cells. This strategy focuses on reducing the intensity of the SASP by limiting the release of pro-inflammatory and proteolytic mediators that disrupt cellular function. By attenuating these signals, it is possible to mitigate the negative impact of senescent cells on the extracellular matrix and neighboring cells, contributing to the partial restoration of skin homeostasis.

From a dermocosmetic perspective, the approach to cellular senescence is evolving toward strategies capable of acting on the biological processes that regulate skin aging. This shift has driven the development of ingredients designed to modulate cellular signaling, reduce the inflammatory impact associated with the SASP, and support the functional balance of the skin. In this context, innovation is focused on actives capable of specifically targeting these mechanisms, opening new opportunities in the design of formulations aimed at skin longevity.
The following are some ingredients with evidence and potential in this field.

Our active ingredients targeting cellular senescence

NMN (β-Nicotinamide Mononucleotide)

Is a direct precursor of NAD⁺, a coenzyme that plays a key role in cellular longevity mechanisms. Its smaller molecular size may favor enhanced skin penetration, enabling its intracellular conversion into NAD⁺ and the activation of sirtuins (SIRT1, SIRT6), which are involved in cellular repair and homeostasis. In the skin, it has been shown to promote fibroblast proliferation and the synthesis of type I collagen and elastin, contributing to skin regeneration and the maintenance of the extracellular matrix.

NAD⁺ (Nicotinamide Adenine Dinucleotide)

Is an essential coenzyme for ATP production and the regulation of processes related to cellular longevity. Its levels decline with age, a phenomenon associated with cellular senescence. In the skin, adequate NAD⁺ levels support the synthesis of collagen, elastin, and hyaluronic acid, while also improving barrier function and regenerative capacity.

Resveratrol

is a natural polyphenol with strong antioxidant activity, widely studied for its role in cellular longevity and the prevention of skin senescence. It acts by neutralizing reactive oxygen species (ROS), reducing inflammation, and promoting the synthesis of collagen and elastin, thereby helping to maintain the integrity of the extracellular matrix and improve the appearance of aged skin. In addition, it can activate longevity-related pathways such as SIRT-1, which are involved in the response to oxidative stress.

These effects have been supported by various experimental and clinical studies, demonstrating their impact on parameters related to pigmentation and cellular function:

• In vivo: A double-blind, placebo-controlled clinical study in 52 volunteers with topical application of 1% resveratrol for 90 days showed a significant increase in the ΔITA° parameter, indicating skin brightening and reduced pigmentation.

• In vitro: Resveratrol reduced melanin production by up to 50% in B16F10 cells at low concentrations. In human melanocytes, it showed higher efficacy than kojic acid in inhibiting melanogenesis.

PTD-Sirt6 (sh-Polypeptide-138)

Is a recombinant protein based on Sirtuin-6, one of the key longevity-related genes involved in the regulation of cellular aging. This active targets skin senescence at two levels: promoting the selective elimination of senescent cells (senolytic effect) and inhibiting SASP-related inflammatory factors associated with aging. In addition, it incorporates a PTD (Protein Transduction Domain) system that facilitates the penetration of proteins and peptides into the skin, allowing the active to reach target cells.

These effects have been observed in in vitro and ex vivo studies evaluating its impact on cellular senescence:

• Senescence markers:

• • In vitro (H₂O₂-induced senescent cells): inhibition of p21 (↓77.5%) and p16 (↓70.6%)
  • In vitro: reduction of senescent cells + increase in EGF and FGF (associated with “cellular aging inhibition”)

• Senomorphic activity (SASP):

• • In vitro (H₂O₂): inhibition of SASP factors with reported reductions of IL-6 (↓93.8%), IL-8 (↓98.9%), MMP-1 (↓68.9%), and IL-1β (↓89.7%), compared to controls such as fisetin/oleuropein

• Anti-aging studies:

• • Ex vivo: COL1 ↑79.89%, Filaggrin ↑173.01%, Ki-67 ↑23.34% (significant)