Today, I thought I'd point out a couple of papers that touch on different aspects of the overlap between visceral fat tissue and senescent cells in aging. In the first paper, researchers show that the ability of visceral fat tissue to generate the markers of senescence is suppressed when the circulatory system of an old mouse is linked to a younger mouse. All of the ongoing, unresolved arguments over why this sort of modest rejuvenation occurs apply here; my money is still on it being dilution of harmful factors in an aged bloodstream. In the second paper, researchers link yet another aspect of dysfunction in the brain to the presence of senescent cells, in this case disorders such as anxiety and depression that are linked to fat tissue. The senescent cells can be used to explain that association with excess fat tissue.
Excess visceral fat tissue is harmful in many different ways, damaging the body and the brain. It is metabolically active, distorting the normal operation of cellular metabolism and tissue functions throughout the body. Further, it generates chronic inflammation via what appears to be quite a wide variety of mechanisms, from inappropriate cell signaling to DNA debris from dead fat cells. Short bursts of inflammation are a normal part of the response to injury and infection. When those mechanisms become stuck, however, activated without cease for the long term, then they become very damaging. Chronic inflammation accelerates the progression of all of the most common disabling and ultimately fatal age-related conditions. Being overweight speeds up that process.
As ever more of the research community becomes convinced (finally) that senescent cells are an important root cause of degenerative aging, more attention is being directed to all of the inflammatory conditions and states, searching for the senescent cells that no doubt cause a sizable fraction of that inflammation. Even in very old people, it is thought that there are only a small number of senescent cells present in tissues - perhaps a few percent of all cells at most. Yet these errant cells have a sizable detrimental effect, as the damage they do is mediated by the signal molecules that they generate, influencing the behavior of countless other cells near and far. Pro-inflammatory signals are one of the better understood consequences of cellular senescence, and the reason why these cells are a significant cause of inflammatory disease in old age.
Thus fat tissue doesn't have create many more senescent cells, in absolute numbers, in order to place a significant burden of damage and dysfunction on the rest of the body. Sadly, it does indeed create those cells. We can quite accurately say that being overweight results in an acceleration of aging, a consequence reflected in mortality rates, disease risk, and medical expenditure. The overweight and the obese have shorter, less healthy, more expensive lives, with all of those disadvantages scaling with the amount of excess visceral fat tissue, and the length of time it is carried. That isn't all down to senescent cells - there are plenty of other issues to consider in the harmful biochemistry of large amounts of fat tissue. I am sure that the development of senolytic therapies to destroy senescent cells will lead to a quantification of just how much of the damage done by being overweight is down to cellular senescence. Building therapies is the fastest way to obtain answers to this sort of question.
Visceral adipose tissue (VAT) inflammation plays a central role in longevity and multiple age-related disorders. Cellular Senescence (SEN) is a fundamental aging mechanism that contributes to age-related chronic inflammation and organ dysfunction, including VAT. Recent studies using heterochronic parabiosis models strongly suggested that circulating factors in young plasma alter the aging phenotypes of old animals. Our study investigated if young plasma rescued SEN phenotypes in the VAT of aging mice.
With heterochronic parabiosis model using young (3 months) and old (18 months) mice, we found significant reduction in the levels pro-inflammatory cytokines and altered adipokine profile that are protective of SEN in the VAT of old mice. These data are indicative of protection from SEN of aging VAT by young blood circulation. Old parabionts also exhibited diminished expression of cyclin dependent kinase inhibitors (CDKi) genes p16 (Cdkn2a) and p21 (Cdkn1a/Cip1) in the VAT.
In addition, when exposed to young serum condition in an ex-vivo culture system, aging adipose tissue-derived stromovascular fraction cells (SVFs) produced significantly lower amounts of pro-inflammatory cytokines (Mcp-1 and IL-6) compared to old condition. Expressions of p16 and p21 genes were also diminished in the old SVFs under young serum condition. Finally, in 3T3 pre-adipocytes culture system; we found reduced pro-inflammatory cytokines (Mcp-1 and IL-6) and diminished expression of CDKi genes in the presence of young serum compared to old serum. In summary, current study demonstrates that young milieu is capable of protecting aging adipose tissue from SEN and thereby inflammation.
Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16Ink4a-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin.
We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs. Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed "accumulation of lipids in senescence." Clearing senescent cells from high fat-fed or leptin receptor-deficient obese mice restored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.