Aging is associated with impaired triggering of TRPV3-mediated cutaneous vasodilation: a crucial process for local heat exposure.

Sensing temperature is vitally important to adapt our body to environmental changes. Local warm detection is required to initiate regulation of cutaneous blood flow, which is part of the peripheral thermoregulatory mechanisms, and thus avoid damage to surrounding tissues. The mechanisms mediating cutaneous vasodilation during local heat stress are impaired with aging. However, the impact of aging on the ability of the skin to detect subtle thermal changes is unknown. Among heat-activated cation channels, transient receptor potential vanilloid 3 (TRPV3) is a thermo-sensor predominantly expressed on keratinocytes and involved in local vascular thermoregulatory mechanisms of the skin in young mice. In the present study, using a murine in vivo model of local heat exposure of the skin, we showed that heat-induced vasodilation was reduced in old mice associated with reduced expression of TRPV3 channels. We also found a decrease in expression and activity of TRPV3 channel, as well as reduced TRPV3-dependent adenosine tri-phosphate release in human primary keratinocytes from old donors. This study shows that aging alters the epidermal TRPV3 channels, which might delay the detection of changes in skin temperature, thereby limiting the mechanisms triggered for local vascular thermoregulation in the old skin.

Alpha-Lipoic Acid Supplementation Restores Early Age-Related Sensory and Endothelial Dysfunction in the Skin.

Many changes characterize skin aging, and the resulting dysfunctions still constitute a real challenge for our society. The aim of this study was to compare the skin aging of two rat strains, Wistar and Brown Norway (BN), considered as "poorly aging" and "healthy aging" models, respectively, and to assess the effect of alpha-lipoic acid (LPA), especially on skin microcirculation. To this purpose, various skin characteristics were studied at 6, 12, and 24 months and compared to the results of LPA treatment performed at 12 or 24 months. Skin aging occurred in both strains, but we showed an early occurrence of different age-related disorders in the Wistar strain compared to BN strain, especially regarding weight gain, glycemia dysregulation, basal skin perfusion, endothelial function, and skin resistance to low pressure. LPA treatment tended to improve skin resistance to low pressure in BN but not in Wistar despite the improvement of basal skin perfusion, endothelial function, and skin sensory sensitivity. Overall, this study confirmed the healthier aging of BN compared to Wistar strain and the positive effect of LPA on both general state and skin microcirculation.

MiR-30a-5p Alters Epidermal Terminal Differentiation during Aging by Regulating BNIP3L/NIX-Dependent Mitophagy.

Chronological aging is characterized by an alteration in the genes' regulatory network. In human skin, epidermal keratinocytes fail to differentiate properly with aging, leading to the weakening of the epidermal function. MiR-30a is particularly overexpressed with epidermal aging, but the downstream molecular mechanisms are still uncovered. The aim of this study was to decipher the effects of miR-30a overexpression in the human epidermis, with a focus on keratinocyte differentiation. We formally identified the mitophagy receptor BNIP3L as a direct target of miR-30a. Using a 3D organotypic model of reconstructed human epidermis overexpressing miR-30a, we observed a strong reduction in BNIP3L expression in the granular layer. In human epidermal sections of skin biopsies from donors of different ages, we observed a similar pattern of BNIP3L decreasing with aging. Moreover, human primary keratinocytes undergoing differentiation in vitro also showed a decreased expression of BNIP3L with age, together with a retention of mitochondria. Moreover, aging is associated with altered mitochondrial metabolism in primary keratinocytes, including decreased ATP-linked respiration. Thus, miR-30a is a negative regulator of programmed mitophagy during keratinocytes terminal differentiation, impairing epidermal homeostasis with aging.

Maintenance of Chronological Aging Features in Culture of Normal Human Dermal Fibroblasts from Old Donors.

Chronological aging is defined as a time-dependent decline of tissue homeostasis which severely impacts skin. Understanding the mechanisms of skin aging is an active research area limited by the lack of relevant in vitro models. Being a component of aging, replicative or stress-induced senescence is repeatedly used to mimic skin aging in vitro, thus presenting only a partial view of the complexity of aging. Herein, we aimed to clarify whether primary normal human dermal fibroblasts retained age-related characteristics when cultured in 2D monolayer, and could be used as a relevant model for aging research. We compared three groups of fibroblasts isolated from different aged donors. We observed strongly decreased population doubling capacities, a reduced clonogenic ability, an impairment in extracellular matrix production together with modifications of respiratory metabolism with an increase in age. These disruptions were particularly marked when comparing fibroblasts isolated from old individuals (over 70 years old) to those isolated from young individuals (18-37 years old), while cells from middle-aged donors exhibited an intermediate profile. These alterations of cell features can be related to the signs of dermis aging, thus showing that cultured primary cells indeed retain some characteristics of the original tissue from which they were extracted.