Evidence for Some of the Burden of Fat Tissue to Result from Increased Levels of Cellular Senescence
Excess visceral fat tissue is very bad for long-term health. Being obese is by some measures as harmful as a smoking habit when it comes to remaining life expectancy. Even modest amounts of excess weight have a measurable negative impact on the future trajectory of health and longevity. There is an enormous mountain of data to support these points, ranging from large human studies to simple but compelling experiments in which the surgical removal of fat from mice leads to extended life spans. Unfortunately we evolved in an environment of scarcity and so find it a challenge to stay slim in an environment of plenty; this is a high class problem to have in exchange for an end to unavoidable famine and malnutrition, but a problem nonetheless.
One of the contributing causes of degenerative aging is the growing presence of senescent cells in tissues. While investigating the effects of changes in the amount of fat tissue in mice, researchers here find evidence to suggest that some portion of the damage done by fat tissue occurs because it hosts many more senescent cells than would otherwise be present in the body. These cells produce a mix of inflammatory signals, and may well be a sizable cause of the well-known link between visceral fat and increased inflammation. Chronic inflammation alone drives a faster progression of most of the common fatal age-related conditions, and that is without considering all of the other damage done due to the signaling produced by senescent cells.
With obesity rates on the rise, more individuals are attempting to lose weight for improved health. Unfortunately, the vast majority of weight loss attempts are short-lived and are followed by weight gain. That is, for individuals that successfully achieve weight loss of at least 10%, approximately 80% will regain the weight in the first year alone. Repeated attempts at weight loss results in a phenomenon referred to as weight cycling. As global rates of obesity increase, weight cycling is becoming increasingly common. Unfortunately, clinical studies have produced conflicting results with some studies suggesting that weight cycling may decrease lifespan while others suggest that weight cycling has no negative effect. Review of these clinical studies suggests that inclusion of confounding factors, such as unintentional weight loss, likely accounts for the discrepancies and that further research is needed.
In attempts to perform a controlled animal study, our laboratory set out to evaluate the impact of lifelong weight cycling on longevity in mice. Results of this study showed that weight-cycled mice lived significantly longer than obese mice (801 vs 544 days), suggesting that periodic, repeated, weight loss attempts were preferable to no weight loss attempts in obese mice. To better understand the molecular changes that occur during weight cycling, we analyzed cellular senescence via senescence-associated β-galactosidase staining in white adipose tissue (WAT) and circulating levels of activin A, a recently identified marker of cellular senescence.
In this study and in agreement with other studies, we show that obesity induced by a high fat (HF) diet results in a significant increase in senescent cells in WAT compared to low fat (LF) controls. Circulating activin A levels were also increased in the HF group compared to the LF controls. Importantly, our data indicate that 28 days of weight loss are sufficient to significantly reduce the number of senescent cells as shown by significantly reduced activin A levels and a significant reduction in senescent beta-galactosidase stained cells in inguinal and retroperitoneal WAT depots. Of note, since inguinal and retroperitoneal WAT were the most responsive to the weight loss, there appears to be a depot specific difference in cellular senescence in response to this dietary manipulation.
Recently a comprehensive study identified activin A as a marker for cellular senescence in humans and mice. In this study, it was determined that i) human senescent fat cell progenitors release activin A, ii) activin A impedes the normal function of stem cells and fat tissue, iii) older mice have higher levels of activin A in both their blood and fat tissue than young mice, and iv) eliminating senescent cells from mice leads to lower levels of activin A. Since most procedures used to determine senescent cell accumulation require tissue collection, the discovery of a circulating marker of cellular senescence represents an important step for detection of senescent-related disease. This is particularly important in a clinical setting since blood is relatively easy to collect. Research has shown there is a correlation between obesity and increased cellular senescence, which may account for increased mortality and progression of age-related diseases. Thus, the possibility of senolytic treatment (agents that clear senescent cells), particularly in WAT, has been suggested as a potential therapeutic target. For those reasons, clearance of senescent cells in WAT with senolytic agents or, as we show here, with dietary manipulation, may be a promising approach for treatment of metabolic syndrome, type 2 diabetes, and other age-related complications.