Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease

Abstract

Recent mouse model experiments support an instrumental role for senescent cells in age-related diseases and senescent cells may be causal to certain age-related pathologies. A strongly supported hypothesis is that extranuclear chromatin is recognized by the cyclic GMP–AMP synthase-stimulator of interferon genes pathway, which in turn leads to the induction of several inflammatory cytokines as part of the senescence-associated secretory phenotype. This sterile inflammation increases with chronological age and age-associated disease. More recently, several intracellular and extracellular metabolic changes have been described in senescent cells but it is not clear whether any of them have functional significance. In this review, we highlight the potential effect of dietary and age-related metabolites in the modulation of the senescent phenotype in addition to discussing how experimental conditions may influence senescent cell metabolism, especially that of energy regulation. Finally, as extracellular citrate accumulates following certain types of senescence, we focus on the recently reported role of extracellular citrate in aging and age-related pathologies. We propose that citrate may be an active component of the senescence-associated secretory phenotype and via its intake through the diet may even contribute to the cause of age-related disease.

Dyskeratosis Congenita Links Telomere Attrition to 
Age-Related Systemic Energetics

“…Trivial explanations such as cell lysis and exosome release are inconsistent with the normal levels of the cytoplasmic metabolites urate and AKG in DC plasma. Significantly, virtually all aspects of the DC profile increase with chronological age and agerelated disease (22,23,27,42,48). High isocitrate, aconitate and malate are associated with frailty, cardiovascular disease and mortality in humans (42,45,46).…”

“…The ESM metabolite citrate is particularly interesting because its uptake has been implicated in ageing, caloric restiction, type 2 diabetes, blood pressure, heart rate, memory, adipocyte inflammation, epigenetic regulation and cancer (reviewed in (27)) and so we initially investigated this metabolite.…”

Downregulation of Sirt6 by CD38 promotes cell senescence and aging

“…The senescence-associated secretary phenotype (SASP) is the key feature of aging cells and includes a series of proinflammatory cytokines, chemokines and proteases [52][53][54]. Senescent cells secrete a series of inflammatory cytokines, chemokines, growth factors and matrix remodeling factors that alter local tissue environments [52][53][54][55]. In our study, serum IL-α, IL-1β, IL-6, IL-10, IL-17A, IL-27 and TNF-α levels, as well as ALT, CK and LDH levels, were significantly increased in D-gal-treated mice.…”

“…Proinflammatory cytokines, such as TNF-α, amplifies senescence-associated inflammation and induce senescence [ 58 ]. Additionally, metabolism plays an essential role in cell senescence, and alternative metabolism is an important part of cell senescence [ 55 , 59 ]. The metabolic alterations of glucose, lipid, glutamine and NAD+ can facilitate or inhibit cell senescence [ 9 ].…”

Differentially Expressed Genes and Molecular Susceptibility to Human Age-Related Diseases

“…Moreover, many other pathologies can contribute to ARDs: amyotrophic lateral sclerosis, to motoneuronal aging [ 22 ]; mitochondrial dysfunction, to aging as such [ 23 ]; vascular atherosclerosis, to cellular senescence [ 24 ]; hypertension, to vascular aging [ 25 ]; thalassemia, to myelodysplastic syndrome [ 26 ]; cancer, to immune system aging and vice versa [ 27 ]; and circadian rhythm disorder, to aging as such [ 28 ]. Furthermore, some diets enriched for fat [ 29 ], calcium [ 30 ], or citrates [ 31 ] can provoke ARDs, as do long-term hunger, malnutrition, anorexia, and appetite loss [ 32 ]. By contrast, moderate physical exercise [ 33 ], short-term fasting [ 34 ], and low-dose aspirin [ 35 ] can prevent such diseases.…”