In the research here, injections of blood plasma from young rats are shown to improve autophagy and liver function in old rats. This is interesting given the so far mixed evidence for young to old plasma transfer to be beneficial. There is, however, a history of research to show that increased levels of the cellular maintenance processes of autophagy can improve liver function in old rodents. Autophagy normally declines with age, and this appears to contribute to a variety of issues, such as loss of stem cell activity. You might recall that increasing the number of receptors on lysosomes in old rats can improve liver function; lysosomes are the portion of the autophagic infrastructure that break down damaged proteins and structures, and they function more effectively when equipped with more receptors.
The young to old plasma transfusion strategy is an outgrowth of parabiosis research in which the circulatory systems of a young and old individual are linked. This worsens measures of aging in the younger individual and improves them in the older individual. Current opinion in the research community is divided between the hypothesis that factors in young blood improve cell and tissue function, or that factors in old blood harm cell and tissue function. There is evidence for both sides, and the balance has swung back and forth over the past few years.
The study here adds something new, meaning the evidence for beneficial effects of plasma transfer to be primarily mediated by increased autophagy, at least in the liver. This has been demonstrated for calorie restriction and a number of related methods of modestly slowing the aging process in laboratory species - autophagy is clearly important in the hierarchy of biological systems that determine the relationship between environmental circumstances and natural variations in the pace of aging. Given that those approaches fail to extend life in humans and other long-lived species to anywhere near the same degree as occurs in short-lived species, one might speculate that the same unfortunate relationship will apply here. Parabiosis might turn out to be just another way of manipulating some of the beneficial cellular reactions to calorie restriction, achieving the same poor results on life span in humans, but possibly still a useful degree of other benefits to health.
Recent studies showing the therapeutic effect of young blood on aging-associated deterioration of organs point to young blood as the solution for clinical problems related to old age. Given that defective autophagy has been implicated in aging and aging-associated organ injuries, this study was designed to determine the effect of young blood on aging-induced alterations in hepatic function and underlying mechanisms, with a focus on autophagy.
Aged rats (22 months) were treated with pooled plasma (1 ml, intravenously) collected from young (3 months) or aged rats three times per week for 4 weeks, and 3-methyladenine or wortmannin was used to inhibit young blood-induced autophagy. Aging was associated with elevated levels of alanine transaminase and aspartate aminotransferase, lipofuscin accumulation, steatosis, fibrosis, and defective liver regeneration after partial hepatectomy, which were significantly attenuated by young plasma injections.
Young plasma could also restore aging-impaired autophagy activity, while inhibition of the young plasma-restored autophagic activity abrogated the beneficial effect of young plasma against hepatic injury with aging. In vitro, young serum could protect old hepatocytes from senescence, and the antisenescence effect of young serum was abrogated by 3-methyladenine, wortmannin, or small interfering RNA to autophagy-related protein 7. Collectively, our data indicate that young plasma could ameliorate age-dependent alterations in hepatic function partially via the restoration of autophagy.