More Evidence for Cellular Senescence to Mediate Detrimental Effects of Obesity

Excess visceral fat tissue distorts the operation of metabolism, reduces life expectancy, raises risk of age-related disease, and increases lifetime medical costs. Some fraction of these detrimental effects are mediated by cellular senescence: more senescent cells are created than would otherwise be the case, given extra visceral fat. Given that the accumulation of senescent cells is one of the root causes of aging, we might argue that being overweight literally accelerates the aging process. In the open access paper here, researchers explore some of the underlying mechanisms by which senescent cells are generated more readily in obese individuals. It is worth noting, however, that the epidemiological data on weight shows that any increase above a healthy level is harmful. More is worse, but any gain is bad to some degree.

Subcutaneous adipose tissue (SAT) is the largest and best storage site of excess fat in the body provided that new cells can be recruited as needed (hyperplastic obesity). Inappropriate expansion of the adipose cells (hypertrophic obesity) promotes insulin resistance and other obesity-associated metabolic complications and is a consequence of inability to recruit new adipose cells. This has been shown both in vitro and in direct studies of human adipose cell turnover in vivo.

Our previous extensive studies have shown large inter-individual differences in ability of human SAT stromal vascular fraction (SVF) cells to undergo adipogenesis. Furthermore, markers of reduced SAT adipogenesis are associated with genetic predisposition for type 2 diabetes (T2D) and first-degree relatives (FDR), like individuals with manifest T2D, are characterized by hypertrophic obesity. Human SAT contains a pool of adipose progenitor cells but the detailed signals for recruiting new adipose cells and the reasons for the large individual differences are unclear. Bone morphogenetic protein 4 (BMP4) is important for the commitment of mesenchymal progenitor cells into the adipogenic lineage and BMP-signalling is regulated by different secreted inhibitors. We found Gremlin-1 (GREM1) to be an important BMP4 antagonist and increased in hypertrophic obesity. Thus, impaired commitment of progenitor cells could be one reason for the reduced adipogenesis.

Cell senescence is, in part, a consequence of repeated progenitor cell mitogenic expansion and there is a 10% annual cell turnover in human SAT. Cell senescence leads to permanent cell cycle arrest, secretion of different senescence-associated proteins and inhibited cell differentiation. We here characterize mechanisms for the impaired SAT adipogenesis in adult human subjects with hypertrophic obesity including FDR/T2D. A key mechanism for the impaired adipogenesis in hypertrophic obesity / T2D is increased progenitor cell senescence, dysregulated p53 and P16ink4 and secretion of senescence-associated secretory phenotype (SASP) factors antagonizing normal cell adipogenic differentiation.

Link: https://doi.org/10.1038/s41467-019-10688-x

Comments

This is a chicken and egg scenario - hypertrophic fat cells are signalling other cells to become senescent; but equally they became hypertrophic in the first place because their progenitors were senescent. This could be replictive senescence (inevitable with aging) and/or cyctoskeleton and ECM mediated from hyperglycemia (inevitable from diabetes).

Posted by: Mark at July 3rd, 2019 6:48 AM

How about making senescent cells viable again by increasing telomere length? I am now trying to get Fluvastatin and Valsartan for my n=1 study.

"We found that a low-dose combination of fluvastatin and valsartan substantially increased telomerase activity, which significantly correlated with an improvement of endothelial function and a decrease of inflammation/oxidative stress"
https://www.ncbi.nlm.nih.gov/pubmed/26214555

"Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat "Aging-Related Disorders"
https://www.ncbi.nlm.nih.gov/pubmed/31013989

Posted by: Lee at July 3rd, 2019 9:08 AM

@Lee, do you use any metric to see if it's working?

Posted by: Johannes at July 3rd, 2019 1:57 PM

@Johannes
I just ordered the meds today. I will have my flow mediated dilation and C reactive protein tested and compared to before treatment. They did this in the study. Also will see if there is a difference in my blood pressure afterward when not on these meds. Other than that I will just observe for changes in the way I feel, skin appearance, hair greying reversal etc.

Posted by: Lee at July 3rd, 2019 5:29 PM

You can also do a nail blanching test

Posted by: Johannes at July 4th, 2019 8:18 AM

I thought Valsartan had been recalled due to contamination w NDMA. Has the problem been rectified? Or are you just not concerned because of the low dose you will be trying? I have just turned 78 and have begun feeling some of the general and overall effects of aging and am considering experimentation w some of the senolytic-type protocols I've been reading about here. It is most fascinating and encouraging that so much is trying to be done to stave off some of the ravages of old age; albeit frustrating that so much government money is wasted on needless politically motivated projects. And treating disease is such big business government funding is highly unlikely. It has always been 'profits before people.' Shameful and sad...but true.

Posted by: Ann Cappola at July 7th, 2019 9:48 AM

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