Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.

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S-NitrosothiolsS-Nitrosothiols are compounds with the generic structure of RSNO. Under appropriate conditions these compounds decompose to liberate nitric oxide ( ⅐ NO) and the corresponding disulfide (1). It has been suggested that the formation and decay of low molecular weight S-nitrosothiols, such as S-nitrosoglutathione (GSNO) 1 and S-nitrosocysteine (CySNO), may represent a mechanism for the storage or transport of ⅐ NO (2, 3). According to this proposal, S-nitrosothiols are synthesized chemically by reaction of ⅐ NO with thiol. Subsequently, these compounds are transported or diffuse to the site of action. Decomposition of the S-nitrosothiol then leads to ⅐ NO release and the corresponding biological effect. This hypothesis is mainly speculative and remains to be rigorously tested. Little is known about the reaction of ⅐ NO with glutathione (GSH) in vivo; however, the direct reaction of GSH with ⅐ NO does not generate GSNO but forms glutathione disulfide and nitroxyl anion (NO Ϫ ) (4, 5). GSNO is formed only if ⅐ NO is oxidized, by reaction with oxygen, to form ⅐ NO 2 and N 2 O 3 (6). As intracellular oxygen concentrations at the tissue level are in the range of 10 -20 M (7) and as the rate of ⅐ NO oxidation is proportional to the squared power of the ⅐ NO concentration (8), it is likely that the oxidation of ⅐ NO by oxygen in vivo is a slow and insignificant process (4). Evidence for the formation of S-nitrosothiols from endogenous ⅐ NO remains scarce (9). Nevertheless, nitrosylation of protein thiols has been implicated in the ⅐ NO-dependent regulation of many enzymes, including protein kinase C (10) and glyceraldehyde-3-phosphate dehydrogenase (11). It has been reported that normal human serum contains S-nitroso-serum albumin (12, 13) which has been proposed to act as an endogenous regulator of vessel tone (14).Although the physiological relevance of S-nitrosothiols remains to be established, these compounds have been used as donors of ⅐ NO (1, 15, 16). The most commonly employed compounds are GSNO and S-nitroso-N-acetyl-DL-penicillamine (SNAP) (Fig. 1A). Such compounds have been shown to have diverse and remarkable biological effects. For example, SNAP is a potent vasodilator (1) and low concentrations of GSNO have been shown to afford significant protection to the ischemic myocardium (17). It is generally assumed that S-nitrosothiols decompose by homolytic cleavage of the S-N bond (Reaction 1).This process generates ⅐ NO and a thiyl radical, RS ⅐ (18). However, this assumption has not been effectively tested under physiologically relevant conditions. It has been established that S-nitrosothiols are sensitive to both photolytic (19,20) and transition metal ion-dependent breakdown (21) but are stable in the presence of transition metal ion chelators in the dark. The biological activity of S-nitrosothiols may not be exclusively dictated by the release of ⅐ NO as the chemistry of these compounds is complex. S-Nitrosothiols have also been shown to form NO Ϫ , which under appropriate conditions can lead to...

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Significant concentrations of C-3 epimers of 25OHD(2) or 25OHD(3) are commonly found in infants. This can lead to overestimation of 25-OHD levels. Measurements in children less than 1 yr should therefore be performed with an assay that allows accurate detection of 25-OHD in the presence of its C-3 epimers.