Mitochondria are the power plants of the cell, creating the chemical energy store molecule adenosine triphosphate used to power cellular processes. Mitochondrial function declines with age, and the research community is engaged in a variety of approaches that might at least modestly reduce this loss. The supplement urolithin A is known to improve mitochondrial function, though, and as is the case for other approaches, how exactly urolithin A accomplishes this outcome is not fully understood. Most of the ways to modestly improve mitochondrial function, ranging from exercise and calorie restriction through to NAD+ upregulation via vitamin B3 derivatives and MitoQ, may primarily function through improvements to autophagy targeted at mitochondria, improving overall mitochondrial function via improved clearance of damaged and dysfunctional mitochondria. This is by no means a definitive answer, but the supporting evidence is suggestive.
In today's open access paper, researchers show that topical application of urolithin A improves the function of aged skin. It is interesting to compare this with a small study of topical application of low dose rapamycin, another approach to improve autophagy. Increased autophagy (and accompanied improvement in mitochondrial function) has in the past been shown to reduce the pace at which cells become senescent in aged tissues. This allows the immune system to catch up in its task of clearing senescent cells, and thus reduce the harmful burden of senescent cells that contributes to dysfunction in aged tissues. Cellular senescence is known to be important in the aging of skin, and increased autophagy over time is an approach to reducing this contribution to degenerative aging.
The most common visual signs of aging skin are the appearance of wrinkles, skin thinning, hyperpigmentation, sagginess, and dryness. This derives from a combination of biological changes, including a decline in the quantity and quality of structural components of the skin, such as collagen and elastin, as well as dysfunctions in cellular bioenergetics. Indeed, most of the energy to support skin cell health is derived from mitochondria, making mitochondrial dysfunction a key hallmark of skin aging. The aging process impacts immune cells in the skin. This reduces the ability of the skin to cope with excessive inflammation and significantly contributes to the emergence of photoaging. Finally, cellular senescence is emerging as a key additional hallmark that affects skin health as we age, which can be counteracted by removal of the senescent cells (i.e., senolytic effect) or blunting of their detrimental secretome (i.e., senomorphic effect).
Urolithin A (UA) is a promising molecule to explore for its impact on skin longevity, considering its origins as a postbiotic of the gut microbiome that has been shown to both improve mitochondrial health and reduce age-associated inflammation, i.e., inflammaging, when administered orally. UA increases mitophagy, the process of recycling faulty mitochondria, and enhances biomarkers associated with improved mitochondrial function in several models of aging and age-associated conditions. In humans, oral supplementation of UA was shown to be safe, improve mitochondrial function, and increase muscle strength, endurance, and immune decline in clinical studies in middle-aged and elderly subjects. Topical application of UA represents a compelling approach to support skin health and extend skin longevity through its combined effect on multiple hallmarks of cellular aging.
UA was evaluated for its effects on skin health in human skin models and when applied topically to healthy subjects in randomized clinical studies. UA tested in 2D and 3D reconstructed human skin and ex vivo human skin explants showed enhanced mitochondrial respiration, activated mitophagy markers, reduced inflammatory mediators and senescence-associated markers, and increased proteins involved in extracellular matrix structure and epidermal differentiation. In randomized, placebo-controlled clinical studies, UA reduced periorbital wrinkle depth after 8 weeks and attenuated UVB-induced erythema. Skin transcriptomics supported increased extracellular matrix and epidermal development programs together with decreased inflammatory and senescence-associated signaling.
View the full article at FightAging
