Fight Aging!

Something to bear in mind about aging is that while there is a good catalog of mechanisms and processes, it is rarely clear as to how much of any specific manifestation of degenerative aging is due to process A versus process B. The only way to find out is to remove or repair one of the mechanisms of aging in isolation, and see what results. Until quite recently, the only tools that could change the pace of aging involved upregulation of stress response mechanisms, such as via calorie restriction. These approaches produce sweeping changes in metabolism and all processes related to aging. Now, however, senolytic drugs allow researchers to remove only the contribution of senescent cells to aging, and that such a technology exists is the only reason that we know anything about the relative importance of senescent cells to various diseases of aging.

There is no particular reason that the relative importance of a process of aging should stay the same throughout the aging process. Most of the study of aging in animals involves looking at late life outcomes, where damage and dysfunction is extensive. Early adult aging remains more of a mystery, particularly since the effects are in most cases comparatively small, and thus harder to measure. Skin aging is one of the more noticeable early manifestations of aging, but there is all too little that can be said concretely about how the measurable aspects of skin aging from 20 through to 50 connect to the underlying molecular damage of aging, much of which is only accumulating quite slowly in that first half of adult life. Senescent cells in particular are not expected to be present in large enough numbers to produce strikingly harmful effects until quite late in life.

How good is the evidence that cellular senescence causes skin ageing?

Research in recent years has convincingly proven that cell senescence is a pathophysiologically relevant cause of age-associated multimorbidity and functional losses. There is good evidence that senescent cells accumulate in essentially all compartments of the skin during ageing, not only in sun-exposed skin but also during intrinsic ageing of sun-protected skin. A recent systematic review finds a significant association between senescent cell abundance in skin and donor age. However, the present knowledge about senescence accumulation during ageing in important cell types in the skin is incomplete and, for some cell types, non-existent.

A study with 9 patients with diabetic kidney disease recently showed that a short systemic intervention with the senolytic combination of Dasatinib and Quercetin can reduce frequencies of senescent cells (assessed as p16INK4a- and p21WAF1/CIP1-positive cells) not only in adipose tissue but also in the epidermis, together with a reduction in circulating senescence-associated secretory phenotype (SASP) factors. However, effects on skin function or quality were not reported.

Interventions aimed at improving aged skin function in humans so far relied on more indirect measures to reduce skin cell senescence. Dermabrasion is known to promote collagen remodeling and re-epithelialisation. In a small study with geriatric volunteers, it reduced frequencies of senescent fibroblasts in the upper dermis, increased papillary thickness, upregulated IGF1 expression and improved the UVB response in sun-protected aged skin. Senescent fibroblasts in the upper dermis were shown to enhance melanin production and drive skin hyperpigmentation in vitro and ex vivo. Accordingly, 10 volunteers with senile lentigo were treated with microneedle radiofrequency for 6 weeks, which reduced both frequencies of p16INK4a-positive cells in the upper dermis and epidermal pigmentation in the treated area.

More recently, a small randomized prospective clinical trial was performed to test whether topical application of rapamycin in low concentration could reduce senescence markers and improve function and appearance of photoaged skin. Topical rapamycin reduced the expression of p16INK4a consistent with a reduction in cellular senescence. This change was accompanied by an improvement in clinical appearance of the skin and histological markers of aging and by an increase in collagen VII, which is critical to the integrity of the basement membrane.

In conclusion, there is a good amount of pre-clinical and clinical data showing a strong positive correlation between reduction of senescent cells frequencies and functional improvement of skin. Whether senescence of skin cells makes a significant causal contribution to skin ageing can still not be conclusively decided, however. Nonetheless, there is strong evidence existing today to assume that better understanding of cell senescence in skin may lead to a breakthrough in interventions into skin ageing.