Sirtuin Research Continues Apace

A lot of time and money has gone into the study of sirtuins, a class of a few proteins that participate in numerous cellular processes that influence natural variations in aging and longevity. There was something of a big hype cycle over this back a few years, and like all hype cycles centered on alleged approaches to modestly slowing aging through drugs that alter the operation of metabolism, it all came to nothing exciting in the end. A fair chunk of new cellular biochemistry was mapped, a chunk that it has to be said is in fact a tiny, minuscule slice of the overall space of proteins and genes, something like a few billion dollars were spent, and no reliable demonstrations of extended life in higher animals or viable therapies for age-related disease resulted. It is perhaps worth bearing in mind here that the primary goal of the scientific endeavor in the broader field of cell biology is in fact to map every last complex interaction of cellular biochemistry, and applications of that knowledge are secondary at best, a nagging concern that comes up when writing grants, since the rest of the world has an interest in new technologies and better medicines. I exaggerate, but not greatly.

Large research initiatives have inertia once they are underway and established, and so a broad range of investigations into sirtuin biochemistry continue apace today. Even a brief search of published papers on sirtuins and aging turns up more than a dozen publications in the last couple of months, which is a sizable number for any one narrow subtopic in the life sciences. It is all very interesting, but I think we should continue to assume that there is next to nothing here of any real relevance to the treatment of aging as a medical condition. At the very best this is a long, hard road to drugs that make slight adjustments to the course of aging in any given individual, probably not as large as the adjustments you can make yourself via exercise and calorie restriction. Of course the scientific community should continue along the path of gathering complete understanding of cellular biochemistry, all knowledge will be useful eventually, but we should maintain a realistic view of what various portions of that venture can in fact achieve in the near future.

Here are a selection of recent sirtuin-related papers for you to peruse at your leisure, things that I wouldn't normally take any time to point out. But there is always more going on than is individually newsworthy in my eyes.

Reversing stem cell aging (PDF)

SIRT3 and SIRT7 converge at mitochondrial protection to ensure hematopoietic stem cell maintenance. These protective programs are repressed in aged hematopoietic stem cells and reintroduction of SIRT3 or SIRT7 improves the functional capacity of aged hematopoietic stem cells. Thus, SIRT3 and SIRT7 may modulate the aging process by regulating stem cell quiescence and tissue maintenance. It will be of particular interest to establish whether other tissues use the same mechanism for maintaining stem cell quiescence. It will also be important to identify other genes that mediate mitochondrial protein folding stress to regulate stem cell quiescence.

Sirtuins and Proteolytic Systems: Implications for Pathogenesis of Synucleinopathies

Loss of proteostasis associated with a burden and an impairment of the proteolytic pathways is one of the hallmarks of α-synuclein-induced toxicity. Therefore, modulation of the proteolytic molecular pathways that are deregulated appears as a rational strategy to fight against the harmful effects promoted by α-synuclein. Sirtuins are a family of highly conserved NAD+ dependent histone deacetylases that have emerged as central players in several biological processes, such as transcription, apoptosis, DNA repair, stress cellular response and energetic metabolism. The interest in sirtuins, in the context of proteostasis, emerged with the discoveries that sirtuins have the ability to modulate proteostasis, particularly the autophagy degradation pathway, and aging.

Sirtuin function in aging heart and vessels

Age is the most important risk factor for metabolic alterations and cardiovascular accidents. Although class III histone deacetylases, alias Sirtuins, have been appealed as "the fountain of youth" their role in longevity control and prevention of aging-associated disease is still under debate. Indeed, several lines of evidence indicate that sirtuin activity is strictly linked to metabolism and dependent on NAD+ synthesis both often altered as aging progresses.

SIRTain regulators of premature senescence and accelerated aging

Amongst the seven known mammalian sirtuin proteins, SIRT1 has gained much attention due to its widely acknowledged roles in promoting longevity and ameliorating age-associated pathologies. The contributions of other sirtuins in the field of aging are also gradually emerging. Here, we summarize some of the recent discoveries in sirtuins biology which clearly implicate the functions of sirtuin proteins in the regulation of premature cellular senescence and accelerated aging.

Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes

SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases, has been implicated as a key factor in aging-related diseases. However, the role of SIRT6 in chondrocytes has not been fully explored. The purpose of this study was to examine the role of SIRT6 in human chondrocytes by inhibiting SIRT6 in vitro. Depletion of SIRT6 in human chondrocytes caused increased DNA damage and telomere dysfunction, and subsequent premature senescence. These findings suggest that SIRT6 plays an important role in the regulation of senescence of human chondrocytes.

Differential expression of sirtuins in the aging rat brain

Although there are seven mammalian sirtuins (SIRT1-7), little is known about their expression in the aging brain. We tested mRNA and protein expression levels of rat SIRT1-7, and the levels of associated proteins in the brain. Our data shows that SIRT1 expression increases with age, concurrently with increased acetylated p53 levels in all brain regions investigated. SIRT2 and FOXO3a protein levels increased only in the occipital lobe. SIRT3-5 expression declined significantly in the hippocampus and frontal lobe, associated with increases in superoxide and fatty acid oxidation levels, and acetylated CPS-1 protein expression, and a reduction in MnSOD level. While SIRT6 expression declines significantly with age acetylated H3K9 protein expression is increased throughout the brain. SIRT7 and Pol I protein expression increased in the frontal lobe. This study identifies previously unknown roles for sirtuins in regulating cellular homeostasis and healthy aging.

Expression of SIRT1 and SIRT3 varies according to age in mice

Sirtuins (SIRTs) are involved in multiple cellular processes including those related to aging, cancer, and a variety of cellular functions including cell cycle progression, DNA repair, and cellular proliferation. SIRTs have been shown to extend the yeast life span, although there is presently little known about SIRT expression in the organs of mice. In the present study, we were especially interested in identifying differences in SIRT expression between young mice and aged mice. Specifically, we investigated the expression of SIRT1 and SIRT3 in the kidney, lung, skin, adipose tissue, and spleens of 6-month-old and 24-month-old mice using immunohistochemical staining. Compared with that in younger mice, the expression of SIRT1 in 24-month-old rats was increased in kidney, lung, and spleen tissue, while that of SIRT3 was decreased in adipose, kidney, and lung tissue. The results of our study suggest that aging is associated with altered patterns of expression of SIRT1 and SIRT3. In addition, we noted that the expression patterns of SIRT1 and SIRT3 varied by organ. Taken together, the results of this study suggest the possibility that SIRTs may be involved in diseases associated with aging.

SIRT1 in the brain - connections with aging-associated disorders and lifespan

SIRT1, the best studied member of the mammalian sirtuins, has a myriad of roles in multiple tissues and organs. However, a significant part of SIRT1's role that impinges on aging and lifespan may lie in its activities in the central nervous system (CNS) neurons. Systemically, SIRT1 influences energy metabolism and circadian rhythm through its activity in the hypothalamic nuclei. From a cell biological perspective, SIRT1 is a crucial component of multiple interconnected regulatory networks that modulate dendritic and axonal growth, as well as survival against stress. This neuronal activity of SIRT1 is also important for neuronal plasticity, cognitive functions, as well as protection against aging-associated neuronal degeneration and cognitive decline.

SIRT1 Deficiency in Microglia Contributes to Cognitive Decline in Aging and Neurodegeneration via Epigenetic Regulation of IL-1β

Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as the brain ages is an aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we report a mechanistic link between chronic inflammation and aging microglia and a causal role of aging microglia in neurodegenerative cognitive deficits. We showed that SIRT1 is reduced with the aging of microglia and that microglial SIRT1 deficiency has a causative role in aging - or tau-mediated memory deficits via IL-1β upregulation in mice. Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the specific CpG sites on IL-1β proximal promoter. In humans, hypomethylation of IL-1β is strongly associated with chronological age and with elevated IL-1β transcription. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in aging and neurodegenerative diseases.

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