Abstract
Centenarians not only enjoy an extraordinary aging, but also show a compression of morbidity. Using functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC) we identified 1721 mRNAs differentially expressed by centenarians when compared with septuagenarians and young people. Sub-network analysis led us to identify Bcl - xL as an important gene up-regulated in centenarians. It is involved in the control of apoptosis, cellular damage protection and also in modulation of immune response, all associated to healthy aging. Indeed, centenarians display lower plasma cytochrome C levels, higher mitochondrial membrane potential and also less cellular damage accumulation than septuagenarians. Leukocyte chemotaxis and NK cell activity are significantly impaired in septuagenarians compared with young people whereas centenarians maintain them. To further ascertain the functional role of Bcl- xL in cellular aging, we found that lymphocytes from septuagenarians transduced with Bcl-xL display a reduction in senescent-related markers. Finally, to demonstrate the role of BcL-xL in longevity at the organism level, C. elegans bearing a gain of function mutation in the BcL-xL ortholog ced-9, showed a significant increase in mean and maximal life span. These results show that mRNA expression in centenarians is unique and reveals that BcL- xL plays an important role in exceptional aging.
Highlights
The rapidly graying of populations has stimulated governments all over the world to switch the focus of health care, from delivering adequate treatments to patients with acute episodes of single diseases to providing good health to individuals faced with multiple chronic conditions [1]
In individuals who reach the maximum limit of human life span, morbidity is compressed toward the end of life and there is a rapid onset of decline in functional status and organ reserve; centenarians are an example of successful aging [3]
As with the miRNA data [4], we found that the mRNome of centenarians and septuagenarians is very different, with over 12,000 mRNAs expressed differentially between these two populations (Supplementary Fig. 1a)
Summary
The rapidly graying of populations has stimulated governments all over the world to switch the focus of health care, from delivering adequate treatments to patients with acute episodes of single diseases to providing good health to individuals faced with multiple chronic conditions [1]. Some elderly people themselves may provide clues toward how to achieve healthy aging. Over 80% of centenarians delay their first experience of diseases often associated with high mortality till beyond the age of 90 years or escape these morbidities entirely [2]. Centenarians may have better cognitive function and require minimal assistance for activities of daily living compared with younger elderly who exhibit normal aging [3]. In individuals who reach the maximum limit of human life span, morbidity is compressed toward the end of life (that is, health span approximates life span) and there is a rapid onset of decline in functional status and organ reserve; centenarians are an example of successful aging [3]
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