David A Sinclair

Harvard University | Harvard · Genetics

Context: Nicotinamide adenine dinucleotide (NAD) levels decline with aging and age-related decline in NAD has been postulated to contribute to age-related diseases. Objective: We evaluated the safety and physiologic effects of NAD augmentation by administering its precursor, β-nicotinamide mononucleotide (MIB-626, Metro International Biotech, Wo...

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes t...

Technological advancements have facilitated the implementation of realistic, terrestrial-based complex 33-beam galactic cosmic radiation simulations (GCR Sim) to now probe central nervous system functionality. This work expands considerably on prior, simplified GCR simulations, yielding new insights into responses of male and female mice exposed to...

Frailty is quantified as the accumulation of health deficits over an organism’s lifetime and gives a measure of the overall health of an organism. Preliminary studies have found an association between frailty and some of the hallmarks of aging including inflammation and senescence. However, the molecular underpinnings of frailty, and whether the me...

People living with HIV (PLWH) are disproportionately burdened with multimorbidity and decline in physiologic function compared to their uninfected counterparts, but biological mechanisms that differentially contribute to the decline in muscle function in PLWH compared to uninfected people remains understudied. The study site was Brigham and Women’s...

Naturally produced peptides (<100 amino acids) are important regulators of physiology, development, and metabolism. Recent studies have predicted that thousands of peptides may be translated from transcripts containing small open reading frames (smORFs). Here, we describe two peptides in Drosophila encoded by conserved smORFs, Sloth1 and Sloth2. Th...

Background: Cancer survivors often face infertility as a result of ovarian toxicity from cytotoxic chemotherapy drugs, which trigger a cascade of events ultimately causing follicular reserve exhaustion and endocrine disruption. Apart from infertility, this can have severe consequences on women’s health with early-onset menopause and a decline in bo...

Sirtuins are NAD+-dependent protein deacylases involved in metabolic regulation and aging-related diseases. Specific activators for seven human Sirtuin isoforms would be important chemical tools and potential therapeutic drugs. Activators have been described for Sirt1 and act via a unique N-terminal domain of this isoform. For most other Sirtuin is...

Sirtuins are a family of proteins that protect against cellular injury and aging; understanding their evolution should reveal fundamental mechanisms governing longevity. “Early-branching” animals such as sea sponges and jellyfish have been understudied in previous analyses of sirtuin diversity. These organisms not only hold important positions at t...

Epigenetic clocks allow us to accurately predict the age and future health of individuals based on the methylation status of specific CpG sites in the genome and are a powerful tool to measure the effectiveness of longevity interventions. There is a growing need for methods to efficiently construct epigenetic clocks. The most common approach is to...

Heart failure (HF) is the inability of the heart to pump blood sufficiently to meet the metabolic demands of the body. HF with reduced systolic function is characterized by cardiac hypertrophy, ventricular fibrosis and remodeling, and decreased cardiac contractility, leading to cardiac functional impairment and death. Transverse aortic constriction...

Although chronological age correlates with various age-related diseases and conditions, it does not adequately reflect an individual's functional capacity, well-being, or mortality risk. In contrast, biological age provides information about overall health and indicates how rapidly or slowly a person is aging. Estimates of biological age are though...

The Frailty Inferred Geriatric Health Timeline (FRIGHT) and Analysis of Frailty and Death (AFRAID) clocks were developed to predict biological age and lifespan respectively, in mice. Their utility within the context of polypharmacy (≥5 medications), which is very common in older adults, is unknown. In male C57BL/6J(B6) mice administered chronic pol...

The mitochondrial enzyme SIRT3 is an NAD⁺-dependent deacetylase important in cell metabolism, and a decline in its protein expression or activity has been linked with insulin resistance in obesity, ageing and type-2-diabetes. While studies in SIRT3 knockout mice have dramatically improved our understanding of the function of SIRT3, the impact of in...

Epigenetic clocks allow the accurate prediction of age based on the methylation status of specific CpG sites in a variety of tissues. These predictive models can be used to distinguish the biological age of an organism from its chronological age, and are a powerful tool to measure the effectiveness of aging interventions. There is a growing need fo...

Organismal ageing is accompanied by progressive loss of cellular function and systemic deterioration of multiple tissues, leading to impaired function and increased vulnerability to death. Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with agei...

Background: People living with HIV (PLWH) are disproportionately burdened with multimorbidity and decline in physiologic function compared with their uninfected counterparts, but biological mechanisms that differentially contribute to the decline in muscle function in PLWH compared with uninfected people remain understudied. Setting: The study s...

Nicotinamide adenine dinucleotide (NAD⁺), as an emerging regulator of immune responses during viral infections may be a promising therapeutic target for COVID-19. In this Opinion, we suggest that interventions that boost NAD⁺ levels might promote antiviral defense and suppress uncontrolled inflammation. We discuss the association between low NAD⁺ c...

Aging is the single largest risk factor for most chronic diseases, and thus possesses large socioeconomic interest to continuously aging societies. Consequently, the field of aging research is expanding alongside a growing focus from the industry and investors in aging research. This year's 8th Annual Aging Research and Drug Discovery (ARDD) meetin...

Maintaining genomic integrity and stability is crucial for life; yet, no tissue-driven mechanism that robustly safeguards the epithelial genome has been discovered. Epidermal stem cells (EpiSCs) continuously replenish the stratified layers of keratinocytes that protect organisms against various environmental stresses. To study the dynamics of DNA-d...

Epigenetic "clocks" based on DNA methylation (DNAme) are the most robust and widely employed aging biomarker. They have been built for numerous species and reflect gold-standard interventions that extend lifespan. However, conventional methods for measuring epigenetic clocks are expensive and low-throughput. Here, we describe T agmentation-based I...

Calorie restriction (CR) extends lifespan and retards age-related chronic diseases in most species. There is growing evidence that the gut microbiota has a pivotal role in host health and age-related pathological conditions. Yet, it is still unclear how CR and the gut microbiota are related to healthy aging. Here, we report findings from a small lo...

Heart failure (HF) is defined as an inability of the heart to pump blood sufficiently to meet the metabolic demands of the body. HF with systolic dysfunction is caused by a progressive decline in contractile function and chronic hemodynamic overload, and characterized by ventricular hypertrophy and remodeling, neurohormonal compensation mechanisms,...

Developments in life expectancy and the growing emphasis on biological and ‘healthy’ aging raise a number of important questions for health scientists and economists alike. Is it preferable to make lives healthier by compressing morbidity, or longer by extending life? What are the gains from targeting aging itself compared to efforts to eradicate s...

19 20 Calorie restriction (CR) extends lifespan and retards age-related chronic diseases in most 21 species. There is growing evidence that the gut microbiota has a pivotal role in host health 22 and age-related pathological conditions. Yet, it is still unclear how CR and the gut microbiota 23 are related to healthy aging. Here we report findings f...

Heart failure (HF) is defined as an inability of the heart to pump blood adequately to meet the body's metabolic demands. HF with reduced systolic function is characterized by cardiac hypertrophy, ventricular fibrosis and remodeling, and decreased cardiac contractility, leading to cardiac functional impairment and death. Transverse aortic constrict...

Metabolic flexibility is vital for organisms to respond to and survive changes in energy availability. A critical metabolic flexibility regulator is peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), which regulates various transcription factors and nuclear receptors that, in turn, regulate mitochondrial homeostasis and fatty aci...

The molecular characterization of extracellular vesicles (EVs) has revealed a great heterogeneity in their composition at a cellular and tissue level. Current isolation methods fail to efficiently separate EV subtypes for proteomic and functional analysis. The aim of this study was to develop a reproducible and scalable isolation workflow to increa...

Human stem cell-derived extracellular vesicles (EV) provide many advantages over cell-based therapies for the treatment of functionally compromised tissue beds and organ sites. Here we sought to determine whether human embryonic stem cell (hESC)-derived EV could resolve in part, the adverse late normal tissue complications associated with exposure...

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from...

Currently, no pharmacotherapy has been proven effective in treating photoreceptor degeneration in patients. Discovering readily available and safe neuroprotectants is therefore highly sought after. Here, we investigated nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD+), in a retinal detachment (RD) induced p...

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in...

The Geometric Framework for Nutrition (GFN) has revealed that ad-libitum low-protein, high-carbohydrate (LPHC) diets improve cardiometabolic health and extend lifespan in rodents, but it is not known whether these diets are also beneficial for brain health. Here, we utilized previous results from GFN studies and compared hippocampus biology and mem...

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity1–3. Changes to DNA methylation patterns over time form the basis of ageing clocks⁴, but whether olde...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Treatment with nicotinamide mononucleotide (NMN) is a prominent strategy to address the age-related decline in nicotinamide adenine dinucleotide (NAD+) levels for maintaining aspects of late-life health. It is assumed that exogenous NMN is directly incorporated into the NAD+ metabolome in mammals via the canonical recycling pathway. Here, we show t...

The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict the life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is...

Treatment with nicotinamide mononucleotide (NMN) is a prominent strategy to address the age-related decline in nicotinamide adenine dinucleotide (NAD ⁺ ) levels for maintaining aspects of late-life health. It is assumed that exogenous NMN is directly incorporated into NAD ⁺ in mammals by the canonical recycling pathway, however the need for NAD ⁺ i...

Hepatic ischemia/reperfusion (I/R) injury is a leading cause of organ dysfunction and failure in numerous pathological and surgical settings. At the core of this issue lies mitochondrial dysfunction. Hence, strategies that prime mitochondria towards damage resilience might prove applicable in a clinical setting. A promising approach has been to ind...

Naturally produced peptides (<100 amino acids) are important regulators of physiology, development, and metabolism. Recent studies have predicted that thousands of peptides may be translated from transcripts containing small open reading frames (smORFs). Here, we describe two previously uncharacterized peptides in Drosophila encoded by conserved sm...

In this issue of EMBO Molecular Medicine, Stebbing et al validate an artificial intelligence-assisted prediction that a drug used to treat rheumatoid arthritis could be a potent weapon against COVID-19. Using liver organoids infected with SARS-CoV-2, they confirm dual antiviral and anti-inflammatory activities, and show that its administration in f...

SRT1720, a sirtuin1-activator, and metformin (MET), an antidiabetic drug, confer health and lifespan benefits when administered individually. It is unclear whether combination of the two compounds could lead to additional benefits. Groups of 56-week-old C57BL/6J male mice were fed a high-fat diet (HFD) alone or supplemented with either SRT1720 (2 g...

The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient's age. Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those 65. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea, and from there the disease can progress to acu...

The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient’s age. Over 80% of hospitalizations are those over 65 years of age with a greater than 23-fold greater risk of death. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea. Particularly in those over 65, it can progress to pne...

Maternal obesity impacts offspring metabolism. We sought to boost mitochondrial energy metabolism using the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) to treat metabolic impairment induced by maternal and long-term post weaning over-nutrition. Male offspring of lean or obese mothers, fed chow or high fat di...

Main Text (Cell Metabolism 19, 418–430; March 4, 2014) In the originally published version of this article, the number of mice stated to be used for analysis was mistakenly given as 858 instead of 715. This error does not affect the data, analysis, or conclusions reported in the paper. The authors apologize for any confusion that this error may hav...

Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD+). Treatment with the NAD+ metabolic...

The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not...

The DNA repair capacity of human cells declines with age, in a process that is not clearly understood. Mutation of the nuclear envelope protein barrier-to-autointegration factor 1 (Banf1) has previously been shown to cause a human progeroid disorder, Néstor–Guillermo progeria syndrome (NGPS). The underlying links between Banf1, DNA repair and the a...

In mammals, the lack of accurate biomarkers for biological age is a current limitation to identifying novel aging interventions. Molecular biomarkers including DNA methylation hold promise but are invasive and currently expensive. The Frailty Index (FI) quantifies the accumulation of health-related deficits and is fast, cheap, and non-invasive. Stu...

There are numerous hallmarks of aging in mammals, but no unifying cause has been identified. In budding yeast, aging is associated with a loss of epigenetic information that occurs in response to genome instability, particularly DNA double-strand breaks (DSBs). Mammals also undergo predictable epigenetic changes with age, including alterations to D...

All living things experience entropy, manifested as a loss of inherited genetic and epigenetic information over time. As budding yeast cells age, epigenetic changes result in a loss of cell identity and sterility, both hallmarks of yeast aging. In mammals, epigenetic information is also lost over time, but what causes it to be lost and whether it i...

NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+-dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD+ and related metabolites in t...

The accumulation of mitochondrial DNA (mtDNA) mutations is a suspected driver of aging and age-related diseases, but forestalling these changes has been a major challenge. One of the best-studied models is the prematurely aging mtDNA mutator mouse, which carries a homozygous knock-in of a proofreading deficient version of the catalytic subunit of m...

Through his page-turning narrative, Dr. Sinclair invites the reader into the process of scientific discovery and reveals the Information Theory of Aging and new technologies and simple lifestyle changes that have been shown to help us feel younger and stay healthier longer. At once a road map for taking charge of our own health destiny and a bold n...

People aging with HIV infection (PAWH) experience greater impairments in physical and cognitive function, in addition to higher rates of peripheral comorbid conditions (e.g. renal failure, diabetes, bone fracture, hypertension, cardiovascular disease, polypharmacy and multimorbidity). While multifactorial drivers including HIV infection itself, ant...

Female infertility is a common and devastating condition with life-long health, emotional and social consequences. There is currently no pharmacological therapy for preserving oocyte quality during aging, which is the strongest risk factor for infertility. This leads to an age dependent decline in natural conception and IVF success rates. Here, we...

Male fertility and sperm quality are negatively impacted by obesity. Furthermore, recent evidence has shown that male offspring from obese rat mothers also have reduced sperm quality and fertility. Here, we extend work in this area by comparing the effects of both maternal obesity and offspring post-weaning diet-induced obesity, as well as their co...

Ageing is a degenerative process leading to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage. Changes to DNA methylation patterns over time form the basis of an 'ageing clock', b...

The key role of mitochondria in oxidative metabolism and redox homeostasis explains the link between mitochondrial dysfunction and the development of metabolic disorders. Mitochondria's highly dynamic nature, based on alterations in biogenesis, mitophagy, fusion and fission, allows adjusting sequential redox reactions of the electron transport chai...

SIRT1 is an NAD⁺-dependent lysine deacetylase that promotes healthy aging and longevity in diverse organisms. Small molecule allosteric activators of SIRT1 such as resveratrol and SRT2104 directly bind to the N-terminus of SIRT1 and lower the Km for the protein substrate. In rodents, sirtuin-activating compounds (STACs) protect from age-related dis...

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in...

Even though they would have great benefit across research and clinical fields, currently there are no accepted biomarkers of frailty. Cross-sectional studies in humans have identified promising candidates including inflammatory markers such as IL-6, immune markers such as WBC count, clinical markers such as albumin, endocrine markers such as vitami...

A man in his early 60s with myotonic dystrophy type 1 (DM1) and an extensive history of non-melanoma skin cancer presented with multiple pearly, erythematous papules on his face, head, trunk and extremities, clinically consistent with basal cell carcinoma (BCC). Due to the numerous BCC and history of multiple and early-onset BCC, examination was co...

The aging process results in significant epigenetic changes at all levels of chromatin and DNA organization. These include reduced global heterochromatin, nucleosome remodeling and loss, changes in histone marks, global DNA hypomethylation with CpG island hypermethylation, and the relocalization of chromatin modifying factors. Exactly how and why t...

Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) p...

A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1–SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SI...

Strategies to restore levels of the enzyme cofactor nicotinamide adenine dinclueotide (NAD) late in life to maintain health by treatment with NAD precursors, such as nicotinamide mononucleotide (NMN), represent an exciting area of research in aging and age-related diseases. A study in Nature Metabolism provides an answer to the hotly debated yet fu...