Senescent Cells, Inflammation, Telomere Length, and Mortality

Here is an open access commentary on recent research into the damaged biochemistry of extremely old individuals, in which the authors pull together the strands of chronic inflammation, senescent cell accumulation, and erosion of telomere length, all associated with mortality and the progression of degenerative aging, though much more robustly for the first two in that short list:

Human aging is accompanied by a chronic low-grade inflammation, called "inflammaging", a phenomenon associated with frailty, morbidity, and mortality in elderly people. This condition is related to the accumulation of senescent cells in aged tissues through the senescence-associated secretory phenotype (SASP), which includes pro-inflammatory cytokines among its key constituents. A well-known trigger of cellular senescence, closely related to inflammaging, is telomere length shortening. However, while considerable evidence shows that circulating inflammatory markers are predictors of mortality in community-living elderly individuals, there are conflicting results on the role of telomere length.

It was recently demonstrated with a cross-sectional approach that telomere length, measured in the DNA extracted from whole blood of centenarian offspring, centenarians and (semi-)supercentenarians displays a superior maintenance compared to the one measured in community-living elderly subjects. Indeed, telomere length of centenarian offspring is maintained for more than 20 years at a length corresponding to 60 years of age in the general population. Interestingly, the authors observed that while long telomeres might be a prerequisite for exceptional lifespan in humans, they did not predict mortality. Conversely, they confirmed that a multibiomarker score of systemic inflammation, which included anti-cytomegalovirus IgG, IL-6, TNF-α and C-reactive protein levels, was associated with an increased risk of mortality, loss of cognitive function and physical function decline, in normal aging and at extreme old age (up to 110 years).

These data demonstrate that a multiple biomarker index may represent a more powerful predictor of mortality in older adults than a single inflammatory mediator, as also recently shown through a combined measure of interleukin 6 (IL-6) and soluble TNF receptor 1 (sTNFR1). Therefore, the development of reliable measures of inflammatory status is of great interest in clinical practice both as risk assessment tools of age-related chronic diseases, and to monitor clinical progression or as a powerful surrogate biomarker in the research of new anti-inflammatory therapeutics.

Hence, given that inflammation is a consolidated predictor of mortality, it is also important to investigate the sources of this phenomenon and their relative contribution. While it is known that cell senescence and inflammation can drive each other thus causing accelerated aging, these results suggest that blood telomere length might not reflect the phenomenon of accumulation of senescent cells in various tissues and organs. This could be particularly true if accumulating senescent cells will be confirmed as a major source of circulating inflammatory markers in aging. In this context, the development of strategies to remove senescent cells could represent an emerging tool for the suppression of chronic inflammation and to ameliorate human healthy lifespan.



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