Significance: Human blood provides a rich source of information about metabolites that reflects individual differences in health, disease, diet, and lifestyle. The coefficient of variation for human blood metabolites enriched in red blood cells or plasma was quantified after careful preparation. We identified 14 age-related metabolites. Metabolites that decline strikingly in the elderly include antioxidants and compounds involved in high physical activity, including carnosine, UDP-acetyl-glucosamine, ophthalmic acid,1,5-anhydroglucitol, NAD ⁺ , and leucine. Metabolites that increase significantly in the elderly include compounds related to declining renal and liver function. Statistical analysis suggests that certain age-related compounds that either increased or decreased in the elderly are correlated. Individual variability in blood metabolites may lead to identify candidates for markers of human aging or relevant diseases.

Embryonic stem (ES) cells are immortal and present the ability to self-renew while retaining their ability to differentiate. In contrast, most primary cells possess a limited proliferative potential, and when this is exhausted, undergo an irreversible growth arrest termed senescence. In primary cells, senescence can be also triggered by a variety of stress to which ES cells are highly refractory. Here the authors report that the proliferative capacity of murine ES cells closely correlates with high activity of different glycolytic enzymes, elevated glycolytic flux, and low mitochondrial oxygen consumption. The direct relation between glycolytic flux and the ability of ES cells to proliferate is further remarked in experiments where glycolysis or ES cell self-renewal was specifically inhibited. It was previously reported that the upregulation of glycolysis in primary cells results in life span extension. The authors hypothesize that the naturally high glycolytic flux observed in murine ES cells can be responsible for their unlimited proliferative potential.

As human society ages globally, age-related disorders are becoming increasingly common. Due to decreasing physiological reserves and increasing organ system dysfunction associated with age, frailty affects many elderly people, compromising their ability to cope with acute stressors. Frail elderly people commonly manifest complex clinical symptoms, including cognitive dysfunction, hypomobility, and impaired daily activity, the metabolic basis of which remains poorly understood. We applied untargeted, comprehensive LC-MS metabolomic analysis to human blood from 19 frail and nonfrail elderly patients who were clinically evaluated using the Edmonton Frail Scale, the MoCA-J for cognition, and the TUG for mobility. Among 131 metabolites assayed, we identified 22 markers for frailty, cognition, and hypomobility, most of which were abundant in blood. Frailty markers included 5 of 6 markers specifically related to cognition and 6 of 12 markers associated with hypomobility. These overlapping sets of markers included metabolites related to antioxidation, muscle or nitrogen metabolism, and amino acids, most of which are decreased in frail elderly people. Five frailty-related metabolites that decreased—1,5-anhydroglucitol, acetyl-carnosine, ophthalmic acid, leucine, and isoleucine—have been previously reported as markers of aging, providing a metabolic link between human aging and frailty. Our findings clearly indicate that metabolite profiles efficiently distinguish frailty from nonfrailty. Importantly, the antioxidant ergothioneine, which decreases in frailty, is neuroprotective. Oxidative stress resulting from diminished antioxidant levels could be a key vulnerability for the pathogenesis of frailty, exacerbating illnesses related to human aging.

Increased insulin resistance and impaired insulin secretion are significant characteristics manifested by patients with type 2 diabetes mellitus (T2DM). The degree and extent of these two features in T2DM vary among races and individuals. Insulin resistance is accelerated by obesity and is accompanied by accumulation of dysfunctional adipose tissues. In addition, dysfunction of pancreatic β-cells impairs insulin secretion. T2DM is significantly affected by aging, as the β-cell mass diminishes with age. Moreover, both obesity and hyperglycemia-related metabolic changes in developing diabetes are associated with accumulation of senescent cells in multiple organs, that is, organismal aging. Cellular senescence is defined as a state of irreversible cell cycle arrest with concomitant functional decline. It is caused by telomere shortening or senescence-inducing stress. Senescent cells secrete proinflammatory cytokines and chemokines, which is designated as the senescence-associated secretory phenotype (SASP), and this has a negative impact on adipose tissues and pancreatic β-cells. Recent advances in aging research have suggested that senolysis, the removal of senescent cells, can be a promising therapeutic approach to prevent or improve aging-related diseases, including diabetes. The attenuation of a SASP may be beneficial, although the pathophysiological involvement of cellular senescence in diabetes is not fully understood. In the clinical application of senotherapy, tissue-context-dependent senescent cells are increasingly being recognized as an issue to be solved. Recent studies have observed highly heterogenic and complex senescent cell populations that serve distinct roles among tissues, various stages of disease, and different ages. For example, in high-fat-diet induced diabetes with obesity, mouse adipose tissues display accumulation of p21^Cip1-highly-expressing (p21^high) cells in the early stage, followed by increases in both p21^high and p16^INK4a-highly-expressing (p16^high) cells in the late stage. Interestingly, elimination of p21^high cells in visceral adipose tissue can prevent or improve insulin resistance in mice with obesity, while p16^high cell clearance is less effective in alleviating insulin resistance. Importantly, in immune-deficient mice transplanted with fat from obese patients, dasatinib plus quercetin, a senolytic cocktail that reduces the number of both p21^high and p16^high cells, improves both glucose tolerance and insulin resistance. On the other hand, in pancreatic β cells, p16^high cells become increasingly predominant with age and development of diabetes. Consistently, elimination of p16^high cells in mice improves both glucose tolerance and glucose-induced insulin secretion. Moreover, a senolytic compound, the anti-Bcl-2 inhibitor ABT263 reduces p16^INK4a expression in islets and restores glucose tolerance in mice when combined with insulin receptor antagonist S961 treatment. In addition, efficacy of senotherapy in targeting mouse pancreatic β cells has been validated not only in T2DM, but also in type 1 diabetes mellitus. Indeed, in non-obese diabetic mice, treatment with anti-Bcl-2 inhibitors, such as ABT199, eliminates senescent pancreatic β cells, resulting in prevention of diabetes mellitus. These findings clearly indicate that features of diabetes are partly determined by which or where senescent cells reside in vivo, as adipose tissues and pancreatic β cells are responsible for insulin resistance and insulin secretion, respectively. In this review, we summarize recent advances in understanding cellular senescence in adipose tissues and pancreatic β cells in diabetes. We review the different potential molecular targets and distinctive senotherapeutic strategies in adipose tissues and pancreatic β cells. We propose the novel concept of a dual-target tailored approach in senotherapy against diabetes.

Dementia is caused by factors that damage neurons. We quantified small molecular markers in whole blood of dementia patients, using nontargeted liquid chromatography–mass spectroscopy (LC-MS). Thirty-three metabolites, classified into five groups (A to E), differed significantly in dementia patients, compared with healthy elderly subjects. Seven A metabolites present in plasma, including quinolinic acid, kynurenine, and indoxyl-sulfate, increased. Possibly they act as neurotoxins in the central nervous system (CNS). The remaining 26 compounds (B to E) decreased, possibly causing a loss of support or protection of the brain in dementia. Six B metabolites, normally enriched in red blood cells (RBCs), all contain trimethylated ammonium moieties. These metabolites include ergothioneine and structurally related compounds that have scarcely been investigated as dementia markers, validating the examination of RBC metabolites. Ergothioneine, a potent antioxidant, is significantly decreased in various cognition-related disorders, such as mild cognitive impairment and frailty. C compounds also include some oxidoreductants and are normally abundant in RBCs (NADP ⁺ , glutathione, adenosine triphosphate, pantothenate, S -adenosyl-methionine, and gluconate). Their decreased levels in dementia patients may also contribute to depressed brain function. Twelve D metabolites contains plasma compounds, such as amino acids, glycerophosphocholine, dodecanoyl-carnitine, and 2-hydroxybutyrate, which normally protect the brain, but their diminution in dementia may reduce that protection. Seven D compounds have been identified previously as dementia markers. B to E compounds may be critical to maintain the CNS by acting directly or indirectly. How RBC metabolites act in the CNS and why they diminish significantly in dementia remain to be determined.

The human immunodeficiency virus type 1 (HIV-1) Vif plays a crucial role in the viral life cycle by antagonizing a host restriction factor APOBEC3G (A3G). Vif interacts with A3G and induces its polyubiquitination and subsequent degradation via the formation of active ubiquitin ligase (E3) complex with Cullin5-ElonginB/C. Although Vif itself is also ubiquitinated and degraded rapidly in infected cells, precise roles and mechanisms of Vif ubiquitination are largely unknown. Here we report that MDM2, known as an E3 ligase for p53, is a novel E3 ligase for Vif and induces polyubiquitination and degradation of Vif. We also show the mechanisms by which MDM2 only targets Vif, but not A3G that binds to Vif. MDM2 reduces cellular Vif levels and reversely increases A3G levels, because the interaction between MDM2 and Vif precludes A3G from binding to Vif. Furthermore, we demonstrate that MDM2 negatively regulates HIV-1 replication in non-permissive target cells through Vif degradation. These data suggest that MDM2 is a regulator of HIV-1 replication and might be a novel therapeutic target for anti-HIV-1 drug.