Sirtuins Function as the Modulators in Aging-related Diseases in Common or Respectively

INTRODUCTION According to the demographics, the world population over 60 years will double from 605 million to 2 billion people between 2000 and 2050. Aging is a complex process in which the organism and its ability to respond to external stresses become progressive decline. The degenerative aging process is the major underlying cause for aging-related diseases, including hypertension, diabetes, neurodegenerative diseases, cancer and so on [Table 1]. Many factors contribute to aging, for example, increased oxidative stress, changes in gene expression, accumulation of DNA damage.[1] Disorders of metabolism and dysfunctions of key enzymes/proteins in metabolism are also implicated in aging-related diseases. Accumulating studies have revealed that deacetylase Sirtuins exert profound protective functions against aging-related pathologies for the decline of tissues and organs in the elderly, and experimental and genetic studies have linked Sirtuins activity with delaying aging and extending lifespan.[2345]Table 1: Age-related diseases in elderly populationMammalian Sirtuin family contains 7 members (named SIRT1–SIRT7) and is endowed to diverse biological functions in different cellular compartments. Deacetylase activity is the major characteristic of Sirtuins response to the balance of cellular energy and requires NAD+ as the acceptor of an acetyl group from a target acetyl-lysine residue. Lysine acetylation modulates a variety of metabolic processes, such as fatty acid β-oxidation, tricarboxylic acid (TCA) cycle and oxidative phosphorylation located in mitochondria and another metabolism in cytoplasm by targeting key enzymes or proteins.[6] Epigenetic changes of these enzymes/proteins deacetylation by Sirtuins are involved in the regulation of dysfunction correlated to aging. Sirtuins are also recruited to chromatin and directly deacetylate histones such as H4K16, H3K9, H3K14, H1K26 and so on. Besides the major deacetylase activity of Sirtuins (SIRT1–SIRT3), SIRT4–SIRT7 has been detected no or very weak deacetylase activity. SIRT4 and SIRT6 function as mono-ADP-ribosyltransferases, which transfer the ADP-ribosyl moiety to the substrate protein including glutamate dehydrogenase 1, poly (ADP-ribose) polymerase 1 respectively.[78] SIRT4 also has lipoamidase activity that modulates the biological functions of pyruvate dehydrogenase complex[9] and for its deacetylase inhibiting malonyl CoA decarboxylase in lipogenesis.[10] Recently, it has been found that SIRT5 displays demalonylase and desuccinylase activity by removing malonyl or succinyl moiety from target protein, such as carbamoyl phosphate synthase 1.[11] SIRT6 can regulate protein lysine fatty acetylation in endoplastic reticulum as deacetylase.[12] SIRT7 is the least studied Sirtuin family member, but until now it has been investigated that SIRT7 as deacetylase can target substates p53, H3K18, PAF53 and so on.[13] According to studies on Sirtuins, we find that these different Sirtuin members may modulate the aging-related diseases in common or respectively, although they are in different subcellular localization, have different enzymatic activity and variety of secondary effectors or target proteins.[14] In this review, we summarize the regulatory mechanism of Sirtuins on aging as well as in aging-related diseases such as metabolic complications, neurodegenerative diseases and tumorigenesis etc., along with the role of Sirtuins in extending lifespan or longevity. ROLE OF SIRTUINS IN EXTENDING LIFESPAN OR LONGEVITY The relationship between longevity and “calorie restriction (CR)” was demonstrated by experiments in 1989 that life span was extended markedly by limiting calorie intake in rodent growth.[15] Although the role of SIRT1 on longevity per se is not fully convincing because transgenic mice overexpressing SIRT1 did not show to live longer than controls, the efficacy of SIRT1 in protecting mice against age-associated diseases unveils an important role in improving health span and prevention aging. Simic et al. have clarified SIRT1 deacetylates β-catenin and facilitates its accumulation in nucleus leading to transcription of genes for mesenchymal stem cells differentiation,[16] which are declined with aging. Another group has also demonstrated that CR enhances cell survival by inducing SIRT1 protein expression.[17] SIRT3 is involved in dealing with oxidative stress for cells at under CR.[18] Latest SIRT2 has been found a key modulator of aging, and it extends lifespan in BubR1 mice model.[19] These studies indicate that Sirtuins have the healthful characteristic of regulating caloric restriction(definition) and they are perhaps the natural means of consistently extending lifespan and delaying the onset of aging-related pathologies such as obesity, diabetes, dyslipidemia in mammalian. Though there has been emerging debate on the role of Sirtuins in aging and lifespan extension, mounting evidences suggest that Sirtuins are indeed the critical modulators of aging and the aging-related diseases via different signaling pathways.[20] Nuclear factor (NF-kappa B) locates primarily in cytoplasm as a heterodimer and is an important NF. NF-kappa B signaling is a canonical pathway that is stimulated by intracellular and extracellular stress. It has been reported that constitutive stimulation of NF-kappa B signaling may accelerate aging in mice by motif module map analysis.[21] Kawahara et al. have found SIRT6 binds to the RELA subunit of NF-kappa B and deacetylates H3K9 at NF-kappa B targeted gene promoters resulting in decreased NF-kappa B signaling, thus slowing the aging process.[22] Recently, another experiment has been demonstrated that SIRT6 is correlated with collagen metabolism and acts as a critical factor in skin anti-aging through NF-kappa B signaling pathway.[23] These studies have established the connection between NF-kappa B signaling and SIRT6 in anti-aging process. Therefore, SIRT6 also has the characteristic of extending lifespan and delaying