Autophagy is a vital collection of cellular maintenance processes in which proteins and structures are broken down and recycled for their component parts. In short-lived laboratory species, dysfunctional autophagy shortens life span, while increased operation and efficiency of autophagy – as occurs in response to forms of stress such as heat, exercise, and calorie restriction – slows aging and extends life span.
The usual high level view of aging and autophagy is that autophagic activity declines with age, and that this loss of function contributes to cell and tissue dysfunction, and thus also to age-related disease and mortality. The picture is more complex, however. Different component mechanisms of autophagy decline in different ways and at different paces in different tissues, and this is a distinct issue from the question of whether or not autophagy is running at a given pace. The operation of autophagy is actually upregulated with age in at least some tissues. Too much autophagy can cause issues that are just as problematic as those resulting from too little autophagy, because it destroys necessary protein machinery in the cell, thus disrupting normal function.
Today’s research materials present an interesting example of the perils of too much autophagy. Here, this is specifically occurring in fat cells, and the researchers involved identify a protein that appears to regulate this excessive autophagy in older fat tissue. It is known that fat cells change their behavior for the worse with age, and the changes in autophagy noted here may be one of the more important mechanisms in this aspect of aging.
Is turning back the clock in aging fat cells a remedy for lifestyle diseases?
“Adipocytes produce hormones and cytokines that regulate the function of other metabolic organs. Age-related changes in adipose tissue result in metabolic disorders that are closely associated with life-threatening cardiovascular diseases. However, no one really knows what causes adipocyte dysfunction in aged organisms.” The research team decided to focus on autophagy, the process used by cells to eliminate unwanted or dysfunctional cellular components. Previous studies had shown that autophagy plays an important role in the prevention of various age-related disorders and is likely to be involved in the aging process. But most pertinent was the finding that autophagy is essential for the normal function and longevity of normal organs, such as liver or kidney.
“We previously showed that a protein called Rubicon, which inhibits autophagy, is upregulated in aging tissues. We therefore hypothesized that Rubicon likely accumulates in aged adipocytes, decreasing autophagic activity and contributing to the onset of metabolic disorders.” Surprisingly though, the researchers found that Rubicon levels were actually decreased in the adipose tissue of aged mice, resulting in increased autophagic activity. “As a result, the mice developed lifestyle diseases such as diabetes and fatty liver and had significantly higher cholesterol levels, despite being fed the same diet as control animals.” The researchers went on to identify the specific proteins affected by the increased levels of autophagy, showing that supplementation of these proteins restored adipocyte function.
Age-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy
The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.