Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

Abstract

SummaryRecent 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. 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.

Growth differentiation factor 11 worsens hepatocellular injury and liver regeneration after liver ischemia reperfusion injury

“…We have also demonstrated a similar rejuvenating effect of young blood in aged livers. We demonstrated that young plasma reversed agedependent alterations in hepatic function (48). Recent evidence suggests that young blood contains rejuvenating factors that can restore age-related dysfunction.…”

Young plasma attenuates age‐dependent liver ischemia reperfusion injury

“…A similar rejuvenating effect of young plasma has also been demonstrated in aged liver by us. We showed that young plasma reversed age-dependent alterations in hepatic function (13). These observations suggest that exposure to a young environment could prevent or reverse the agedependent decline in the function of critical organ systems.…”

“…Several studies have demonstrated that aging reduces the activation capacity of AMPK signaling, which impairs the maintenance of efficient cellular homeostasis and augments the aging process (33,34). We previously demonstrated that young plasma could restore the age-impaired autophagic activity (13). However, it is unclear whether AMPK/ULK1-mediated autophagy is a mechanism by which young plasma restores autophagy in aged livers.…”

“…Aging is commonly associated with defective autophagic activity, which is a causal mechanism for the age-dependent liver IRI. Furthermore, age-impaired autophagy could be restored by young plasma (13). Therefore, we hypothesized that young plasma could attenuate IRI via restoration of autophagy.…”

Autophagy—A key pathway for cardiac health and longevity

“…This, in turn, generates a negative feedback loop in which the lysosomal retention of damaged mitochondria contributes to higher levels of oxidative stress and enhanced generation of lipofuscin. Ultimately, these events culminate in a loss of autophagic flux and an inability to maintain cellular homeostasis, compromising cell survival . Accumulation of lipofuscin is especially prevalent in senescent cell types, such as cardiomyocytes, and therefore represents a potential threat to myocardial integrity and function.…”