Obesity Makes You Older

There is no question that being overweight or obese plays havoc with the human body. From the simple fact of the strain on joints from carrying around all that weight to the complex interplay between excess fat and the development of diabetes, heart disease, cancer, kidney failure, central nervous system dysfunction, etc. etc.

Now a recent study published in the journal Cell Metabolism, demonstrates that excess fat tissue (adipose tissue) disrupts the normal functioning of a special family of proteins called sirtuins (SIRTs) specifically adipose tissue SIRT1: http://dx.doi.org/10.1016/j.cmet.2012.07.003

Sirtuins have been the focus of intense scrutiny since the discovery that the yeast sirtuin gene, Sir2, functions as a longevity factor. In other words the expression of Sir2 is associated with life span in yeasts. And expression of yeast Sir2 is enhanced during periods of calorie restriction which has led to speculation that mammalian sirtuin proteins may also be associated with longevity associated with calorie restricted diets. The sirtuins function as either deacetylases or ADP ribosylases, and their activity is regulated by the cofactor NAD and thus may serve as sensors of the metabolic state of the cell and organism. Humans possess 7 sirtuin genes SIRT1-SIRT7. Studies have shown that the anti-oxidant compound resveratrol, found at high concentrations in red wine, can enhance sirtuin activity in cells in culture. The story is less clear in whole animals and humans but the potential for resveratrol as an anti-aging compound is left for another discussion.

In the present study it is demonstrated that SIRT1 in adipose tissue functions to protect from inflammation and obesity under normal feeding conditions. This function of SIRT1 delays the progression to metabolic dysfunction that occurs under conditions of dietary stress (e.g. high fat diets) and aging. In mice that have the SIRT1 gene knocked out specifically in adipose tissue, there is a change in the pattern of gene expression in this tissue that is similar to the pattern of changes seen in wild-type mice fed a high-fat diet. This suggests that dietary stress signals to inhibit the activity of SIRT1. Indeed, in this study wild-type mice fed a high-fat diet showed induction of SIRT1 cleavage by the inflammation-activated caspase, caspase-1.

The take home from these studies is that adipose tissue SIRT1 is necessary for the maintenance of metabolic health in adipose tissue. The consumption of a high-fat diet, or consumption of a diet with excessive calories leading to obesity leads to an inactivation of SIRT1 via inflammation-induced cleavage. The loss of SIRT1 function in adipose tissue significantly contributes to the diabetic phenotype consisting of whole-body glucose intolerance and insulin resistance.

Given the potential role for sirtuins in modulating the processes of aging and age-related disease it seems likely that obesity not only leads to diabetes and heart disease, etc. but also likely causes whole body aging. Of course obese individuals generally die from the metabolic complications of diabetes, heart failure, and kidney failure so it may be difficult to ascertain the precise role that loss of adipose tissue sirtuin function plays in the overall consequences of being obese or overweight.