Researchers here use a study of mice with linked circulatory systems to search for factors involved in skin aging. They find that reduced levels of HAPLN1 may be significant in skin aging, as delivery of recombinant HAPLN1 can improve measures of skin aging. The mechanisms of action are hypothesized but remain to be determined. Also remaining to be determined, and unlikely to receive much attention judging by the way this sort of work usually progresses, is the underlying reason why HAPLN1 levels are reduced with age. A molecule by molecule approach to aging doesn't scale: the search for root causes, and efforts to reverse the known root causes of aging, is arguably far more important than a one-by-one focus on the countless consequences of aging.
Heterochronic parabiosis, the parabiotic pairing of two animals of different ages, qualities, or conditions, has been used to provide an experimental system to test the systemic effects of aging, development of age-related diseases, or other age-related parameters. Therefore, we hypothesized that certain systemic factors contribute to the robust regeneration of skin tissues in young animals and inhibit regeneration in old animals. To avoid animal discomfort and mortality owing to parabiosis, the procedure was performed carefully following a precise protocol approved by our animal care committee. To measure changes in the levels of plasma proteins of each parabiont, broad-scale proteomic analysis was performed. In this study, we demonstrated for the first time that hyaluronan and proteoglycan link protein 1 (HAPLN1, previously known as link protein), whose level of expression decreases in mouse sera with age, played a previously unrecognized function: it restored the amounts of collagen and hyaluronic acid (HA), which progressively declined with skin age. HAPLN1 is a structural protein that links HA and proteoglycans, thus promoting the formation of stable water-rich aggregates in the pericellular matrix (PCM). Our studies suggest that HAPLN1 is a key player that reduces or eliminates cellular damage accumulated in aging skin owing to its involvement in multiple regeneration mechanisms, such as anti-oxidation, anti-senescence, and possibly anti-inflammation. Hence, HAPLN1 substitution therapy could be a promising rejuvenating strategy for preventing or restoring aged skin.