Does hypothalamic SIRT1 regulate aging?

Abstract

In virtually all organisms, life expectancy is profoundly affected by caloric intake. For example, dietary restriction (DR; a feeding regimen of fewer calories compared to the ad libitum level without causing malnutrition) has been shown to lengthen, whereas hypercaloric (HC) diet feeding to shorten, lifespan. Recent findings in invertebrates indicate that specialized groups of cells (e.g.: metabolic-sensing neurons) detect changes in caloric intake and convey energy-status-variation signals to other cells in the body to regulate lifespan. In mammals, whether metabolic-sensing neurons govern aging in a cell-non-autonomous fashion is unknown. Yet, this is a captivating and testable hypothesis.

Figure 1.. Age-dependent decline in BAT content/ activity in perigonadal fat depot

The mRNA level of the brown adipose tissue (BAT)-specific gene uncoupling protein 1 (Ucp1) was used as a readout of BAT content/activity in perigonadal fat. Ucp1 mRNA levels in perigonadal fat of 2- and 7-month-old Sirt1^loxP/loxP females fed on a standard chow (SC) diet and 3- and 7- month-old Sirt1^loxP/loxP females fed on a high calorie (HC) diet [22] (n=9 in each group). Individual mRNA levels were normalized to 36B4 mRNA contents. HC-fed mice were fed on a SC diet up to 2 months of age and then switched and maintained on a HC diet. Note that perigonadal BAT content/activity similarly declines with age in SC and HC diet feeding conditions. Statistical analyses were done using two-tailed unpaired Student's t test. * P <0.05.

Figure 2.. Proposed model by which hypothalamic SIRT1 may control lifespan

Hypothalamic neurons control insulin sensitivity in liver and skeletal muscle and the content/activity of brown adipose tissue (BAT) in visceral fat. Recently, we have shown that SIRT1 in hypothalamic POMC neurons governs BAT in perigonadal fat. The model depicted herein predicts that hypothalamic SIRT1 regulates aspects of the metabolic aging process in peripheral organs (e.g.: insulin sensitivity in liver and skeletal muscle and BAT content/activity in fat depots) and by doing so influences the amounts of circulating adipo-, hepato-, and myo-kines which ultimately contribute to changes in organismal lifespan. Experiments aimed at directly testing whether SIRT1 in hypothalamic neurons controls hepatic and/or skeletal muscle insulin sensitivity, and/or exerts any effects on longevity are warranted.