Inter-organ communication is a critical machinery to regulate metabolism and aging.

Inter-organ communication (IOC) is a complex mechanism involved in maintaining metabolic homeostasis and healthy aging. Dysregulation of distinct forms of IOC is linked to metabolic derangements and age-related pathologies, implicating these processes as a potential target for therapeutic intervention to promote healthy aging. In this review, we delve into IOC mediated by hormonal signaling, circulating factors, organelle signaling, and neuronal networks and examine their roles in regulating metabolism and aging.

DMH neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication.

Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMH neurons), that regulates aging and longevity in mice. DMH neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation.

Absolute quantification of nicotinamide mononucleotide in biological samples by double isotope-mediated liquid chromatography-tandem mass spectrometry (dimeLC-MS/MS).

Nicotinamide adenine dinucleotide (NAD) is an essential metabolite for fundamental biological phenomena, including aging. Nicotinamide mononucleotide (NMN) is a key NAD intermediate that has been extensively tested as an effective NAD-boosting compound in mice and humans. However, the accurate measurement of NMN in biological samples has long been a challenge in the field.

Sleep-wake patterns are altered with age, Prdm13 signaling in the DMH, and diet restriction in mice.

Old animals display significant alterations in sleep-wake patterns such as increases in sleep fragmentation and sleep propensity. Here, we demonstrated that PR-domain containing protein 13 (Prdm13)+ neurons in the dorsomedial hypothalamus (DMH) are activated during sleep deprivation (SD) in young mice but not in old mice. Chemogenetic inhibition of Prdm13+ neurons in the DMH in young mice promotes increase in sleep attempts during SD, suggesting its involvement in sleep control.

Aging reduces motivation through decreased expression in the ventral tegmental area.

Age-associated reduced motivation is a hallmark of neuropsychiatric disorders in the elderly. In our rapidly aging societies, it is critical to keep motivation levels high enough to promote healthspan and lifespan. However, how motivation is reduced during aging remains unknown.

Quantification of localized NAD changes reveals unique specificity of NAD regulation in the hypothalamus.

Recently, it has become a consensus that systemic decreases in NAD are a critical trigger for age-associated functional decline in multiple tissues and organs. The hypothalamus, which contains several functionally distinct subregions called nuclei, functions as a high-order control center of aging in mammals. However, due to a technical difficulty, how NAD levels change locally in each hypothalamic nucleus during aging remains uninvestigated.

Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study.

Objective: Nicotinamide adenine dinucleotide regulates various biological processes. Nicotinamide mononucleotide (NMN) increases its intracellular levels and counteracts age-associated changes in animal models. We investigated the safety and efficacy of oral nicotinamide mononucleotide supplementation in older patients with diabetes and impaired physical performance.

Slc12a8 in the lateral hypothalamus maintains energy metabolism and skeletal muscle functions during aging.

Sarcopenia and frailty are urgent socio-economic problems worldwide. Here we demonstrate a functional connection between the lateral hypothalamus (LH) and skeletal muscle through Slc12a8, a recently identified nicotinamide mononucleotide transporter, and its relationship to sarcopenia and frailty. Slc12a8-expressing cells are mainly localized in the LH.

Age-related disruption of the proteome and acetylome in mouse hearts is associated with loss of function and attenuated by elamipretide (SS-31) and nicotinamide mononucleotide (NMN) treatment.

We analyzed the effects of aging on protein abundance and acetylation, as well as the ability of the mitochondrial-targeted drugs elamipretide (SS-31) and nicotinamide mononucleotide (NMN) to reverse aging-associated changes in mouse hearts. Both drugs had a modest effect on restoring the abundance and acetylation of proteins that are altered with age, while also inducing additional changes. Age-related increases in protein acetylation were predominantly in mitochondrial pathways such as mitochondrial dysfunction, oxidative phosphorylation, and TCA cycle signaling.

SIRT1 mediates hypoxic postconditioning- and resveratrol-induced protection against functional connectivity deficits after subarachnoid hemorrhage.

Functional connectivity (FC) is a sensitive metric that provides a readout of whole cortex coordinate neural activity in a mouse model. We examine the impact of experimental SAH modeled through endovascular perforation, and the effectiveness of subsequent treatment on FC, through three key questions: 1) Does the endovascular perforation model of SAH induce deficits in FC; 2) Does exposure to hypoxic conditioning provide protection against these FC deficits and, if so, is this neurovascular protection SIRT1-mediated; and 3) does treatment with the SIRT1 activator resveratrol alone provide protection against these FC deficits? Cranial windows were adhered on skull-intact mice that were then subjected to either sham or SAH surgery and either left untreated or treated with hypoxic post-conditioning (with or without EX527) or resveratrol for 3 days. Mice were imaged 3 days post-SAH/sham surgery, temporally aligned with the onset of major SAH sequela in mice.

Friends and foes: Extracellular vesicles in aging and rejuvenation.

Extracellular vesicles (EVs) are released by many different cell types throughout the body and play a role in a diverse range of biological processes. EVs circulating in blood as well as in other body fluids undergo dramatic alterations over an organism's lifespan that are only beginning to be elucidated. The exact nature of these changes is an area of active and intense investigation, but lacks clear consensus due to the substantial heterogeneity in EV subpopulations and insufficiencies in current technologies.

NAD oscillation and hypothalamic neuronal functions.

A substantial body of evidence shows the importance of nicotinamide adenine dinucleotide (NAD) biosynthesis and its regulation in a wide range of cellular metabolism. The expression of nicotinamide phosphoribosyltransferase (NAMPT) is regulated in a circadian manner by the core clock mechanism and NAD-dependent sirtuins, producing the circadian oscillation of NAD. The hypothalamus is a critical center for the homeostatic regulation of metabolism, circadian rhythm, and age-associated physiology.

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women.

In rodents, obesity and aging impair nicotinamide adenine dinucleotide (NAD) biosynthesis, which contributes to metabolic dysfunction. Nicotinamide mononucleotide (NMN) availability is a rate-limiting factor in mammalian NAD biosynthesis. We conducted a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in postmenopausal women with prediabetes who were overweight or obese.

SS-31 and NMN: Two paths to improve metabolism and function in aged hearts.

The effects of two different mitochondrial-targeted drugs, SS-31 and NMN, were tested on Old mouse hearts. After treatment with the drugs, individually or Combined, heart function was examined by echocardiography. SS-31 partially reversed an age-related decline in diastolic function while NMN fully reversed an age-related deficiency in systolic function at a higher workload.

Author Correction: Slc12a8 is a nicotinamide mononucleotide transporter.

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

Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men.

Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD prevent these disorders in animal models. The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions. However, the safety of NMN in humans have remained unclear.

Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice.

Aging is a significant risk factor for impaired tissue functions and chronic diseases. Age-associated decline in systemic NAD availability plays a critical role in regulating the aging process across many species. Here, we show that the circulating levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) significantly decline with age in mice and humans.

Unconventional Secretion of Adipocyte Fatty Acid Binding Protein 4 Is Mediated By Autophagic Proteins in a Sirtuin-1-Dependent Manner.

Fatty acid binding protein 4 (FABP4) is a leaderless lipid carrier protein primarily expressed by adipocytes and macrophages that not only functions intracellularly but is also secreted. The secretion is mediated via unconventional mechanism(s), and in a variety of species, metabolic dysfunction is correlated with elevated circulating FABP4 levels. In diabetic animals, neutralizing antibodies targeting serum FABP4 increase insulin sensitivity and attenuate hepatic glucose output, suggesting the functional importance of circulating FABP4.

Slc12a8 is a nicotinamide mononucleotide transporter.

Nicotinamide mononucleotide (NMN) is a biosynthetic precursor of NAD known to promote cellular NAD production and counteract age-associated pathologies associated with a decline in tissue NAD levels. How NMN is taken up into cells has not been entirely clear. Here we show that the gene encodes a specific NMN transporter.

Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age-related morphological changes.

Neuromuscular decline occurs with aging. The neuromuscular junction (NMJ), the interface between motor nerve and muscle, also undergoes age-related changes. Aging effects on the NMJ components-motor nerve terminal, acetylcholine receptors (AChRs), and nonmyelinating terminal Schwann cells (tSCs)-have not been comprehensively evaluated.

NAD biosynthesis, aging, and disease.

Nicotinamide adenine dinucleotide (NAD ) biosynthesis and its regulation have recently been attracting markedly increasing interest. Aging is marked by a systemic decrease in NAD across multiple tissues. The dysfunction of NAD biosynthesis plays a critical role in the pathophysiologies of multiple diseases, including age-associated metabolic disorders, neurodegenerative diseases, and mental disorders.

NAD Intermediates: The Biology and Therapeutic Potential of NMN and NR.

Research on the biology of NAD has been gaining momentum, providing many critical insights into the pathogenesis of age-associated functional decline and diseases. In particular, two key NAD intermediates, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been extensively studied over the past several years. Supplementing these NAD intermediates has shown preventive and therapeutic effects, ameliorating age-associated pathophysiologies and disease conditions.

The NAD World 2.0: the importance of the inter-tissue communication mediated by NAMPT/NAD/SIRT1 in mammalian aging and longevity control.

The original concept of the NAD World was proposed in 2009, providing a comprehensive framework to investigate critical issues of biological robustness and trade-offs in mammalian aging and longevity control. Significant progress has been made over the past 7 years, advancing our understanding of the mechanisms by which biological robustness is maintained, and providing extensive support to the concept of the NAD World. Three key organs and tissues have been identified as basic elements in this control system for mammalian aging and longevity: the hypothalamus as the control center of aging, skeletal muscle as an effector, and adipose tissue as a modulator.

It takes two to tango: NAD and sirtuins in aging/longevity control.

The coupling of nicotinamide adenine dinucleotide (NAD) breakdown and protein deacylation is a unique feature of the family of proteins called 'sirtuins.' This intimate connection between NAD and sirtuins has an ancient origin and provides a mechanistic foundation that translates the regulation of energy metabolism into aging and longevity control in diverse organisms. Although the field of sirtuin research went through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an evolutionarily conserved aging/longevity regulator.