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Mitochondrial ribosomal proteins have been identified as longevity regulators in C. elegans and mammalian systems, their role in longevity is linked to mitonuclear protein imbalance and the mitochondrial unfolded protein response.

Increased expression of sirtuin proteins has been shown to enhance lifespan in several organisms. New data indicate that some of the reported effects may have been due to confounding factors in experimental design. Here, experts discuss the significance of these data for research into ageing. See Letter p.482

Using a zebrafish-based screen, Civiletto and colleagues identify the herb-derived metabolites thymol and carvacrol as activators of autophagy and mitophagy, demonstrating their therapeutic potential in C. elegans and mouse models.

Li et al. uncover a lysosomal surveillance response whereby intestinal lumen deacidification induces a transcriptional programme that boosts lysosomal activity and improves protein aggregate clearance in multiple worm disease models, extending healthspan.

Thymocytes are screened by two processes, termed positive and negative selections, which are permissive only for immature thymocytes with intermediate avidity to the selecting ligands. Here the authors show that the nuclear receptor NCoR1 suppresses Bim1 to inhibit negative selection and promote thymocyte survival.

The authors highlight inconsistencies and divergencies in the literature reporting data on indirect calorimetry for studies on whole-body energy homeostasis, and propose harmonization of standards to facilitate data comparison and interpretation across different datasets.

Amyloid-β peptide proteopathies disrupt mitochondria, and restoring mitochondrial proteostasis reduces protein aggregation in animal models of amyloid-β disease.

Dysfunctional mitochondria are implicated in rare, inherited mitochondrial diseases as well as a variety of common age-related disorders. Here, Auwerx and colleagues provide an overview of diseases that affect mitochondria, highlight strategies for therapeutically intervening in mitochondrial pathways and discuss screening strategies for drug identification.

Auwerx and colleagues review recent advances in mitochondrial genetics, proteomics and biochemistry that emphasize the far-reaching impact of mitochondrial genetic variation and the role of mitochondria as finely tuned signalling hubs.

Roy et al. quantify the impact of a high-fat diet across genetically diverse strains of mice, revealing a generally negative effect on lifespan but also a wide variability.

The recent awareness that bile acids act as complex metabolic integrators and signalling factors has led to the recognition of bile-acid signalling as a potential novel therapeutic target in metabolic disease. Thomas and colleagues overview the metabolic roles of bile acids and discuss approaches to modulate their signalling pathways in the treatment of disorders including obesity, type 2 diabetes, hypertriglyceridaemia and atherosclerosis.

The authors show that sphingolipids, a class of fat molecules, accumulate in skeletal muscle during aging. They demonstrate that reducing sphingolipids improves age-related fitness in mice by enhancing the myogenic response of muscle and present genetic evidence that these findings may also translate to humans.

Benegiamo et al. identify genetic variants of the mitochondrial supercomplex assembly factor COX7A2L in the skeletal muscle of mice and humans that promote cardiorespiratory fitness.

The metallome is crucial for normal cell functioning but remains largely overlooked in mammals. Here the authors analyze the metallome and copper and zinc isotope compositions in aging mice and show networks of interactions that are organ-specific, age-dependent, isotopically-typified and associated with a wealth of clinical and molecular traits.

As most mitochondrial proteins are encoded in the nucleus, mitochondrial activity requires efficient communication between the nuclear and mitochondrial genomes. This is mediated by nucleus-to-mitochondria (anterograde), mitochondria-to-nucleus (retrograde) and mitonuclear feedback signalling, as well as the integrated stress response and extracellular communication, which regulate homeostasis and, consequently, healthspan and lifespan.

Sirtuins are a family of deacetylases that target histones and proteins in several cellular compartments. Sirtuins are crucial regulators of energy homeostasis, as they detect physiological changes in energy levels and modulate glucose and lipid metabolism accordingly. As such, they affect health in a pleiotropic manner.

Vannini and colleagues report that an age-associated decline in nicotinamide adenine dinucleotide levels is associated with mitochondrial dysfunction and reduced antitumor efficacy of chimeric antigen receptor T cells derived from older adults.

Stressed mitochondria activate multiple defense pathways to improve health. Li et al. show that the acetyltransferases CBP/p300 play a central role in mitochondrial stress signaling that defends mitochondrial function and promotes health and longevity.

Antidiabetic drugs that activate the protein PPARγ had a bright start but soon lost their appeal because of undesirable side effects. Subtle modifications may once again make them suitable for treating diabetes.

The naturally occurring compound urolithin A has been found to promote mitophagy, thereby increasing lifespan in worms and improving skeletal muscle activity in rodents.

Changes in protein or histone acetylation are key integrators of physiological processes such as the circadian clock, cell cycle and gene regulation. In this Review, the authors describe the role of reversible acetylation in metabolic control and how these processes contribute to adaptive cellular and organismal homeostasis. The potential for modulating these pathways as a treatment for various metabolic diseases is also discussed.

The transcriptional coregulators YAP/TAZ are shown to directly control leptin gene transcription, thereby uncoupling adipose tissue mass from leptin levels.

Bevers and Litovchenko et al. sequence mitochondrial genomes from 169 different inbred Drosophila melanogaster strains to reveal mitochondrial population structure as well as links between mitochondrial haplotypes and metabolic variation in flies.

Understanding the genetic and phenotypic architecture of health and disease is vital to the identification of novel therapeutic targets and therapies. Here, Nadeau and Auwerx review the fundamentals of genotype–phenotype relations in mouse models and discuss how the integration of human and mouse genetic research remains essential to understanding disease pathogenesis, identifying potential therapeutic targets and developing new therapies

Genetic or pharmacological inhibition of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase increases NAD⁺ and improves mitochondrial function in nematodes and mice, and may have therapeutic potential in kidney and liver disease.

The nuclear receptors REV-ERB-α and REV-ERB-β are indispensible for the coordination of circadian rhythm and metabolism; mice without these nuclear receptors show disrupted circadian expression of core circadian clock and lipid homeostatic gene networks.

Enormous differences exist between human studies, which show a strong association of low vitamin D status with obesity, and mouse data, where low vitamin D signalling causes resistance to obesity. Understanding these discrepancies may provide better insight into the spectrum of activities of vitamin D and should be of interest considering the world epidemic of obesity and the metabolic syndrome.

Botanical extracts offer a valuable resource for identifying therapies. Zumerle, Sarill et al. show that a standardized extract of Salvia haenkei extends lifespan and healthspan in naturally aged mice by modulating inflammation and cellular senescence, and identify the constituent component luteolin as a senomorphic that disrupts the p16–CDK6 interaction.

Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Here, Park et al. identify LETMD1 as a mitochondrial matrix protein enriched in brown adipose tissue (BAT) and reveal a crucial role for it in maintaining brown adipocyte mitochondrial OXPHOS and thermogenesis upon cold stimulus.

This Review examines how hallmarks of aging manifest in the skin and interact with systemic aging, positioning the skin as both an indicator and driver of age-related physiological decline.

Changes in chromatin structure have been linked to organismal ageing. Here the authors show that altered histone expression and mitochondrial stress during C. elegans development result in chromatin changes and a cytosolic stress response that affects organismal longevity, and depends on HSF-1 and the chromatin remodeller, ISW-1.

Auwerx and colleagues review the fundamentals of NAD⁺ metabolism and its roles in organismal health and disease.

Before leaving the body, cholesterol is converted to bile acids. Two studies implicate the nuclear receptor SHP as a major player in bile-acid production—but not the only one.

A reduction in mitochondrial activity and the subsequent decrease in energy expenditure contribute substantially to metabolic dysfunction in aging, insulin resistance and diabetes. Enhancing mitochondrial activity could improve metabolic homeostasis.

AMP-activated protein kinase (AMPK) is shown to transcriptionally regulate genes involved in controlling energy metabolism in skeletal muscle by acting together with the NAD⁺-dependent deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD⁺ levels, resulting in the deacetylation and activation of the SIRT1 downstream target PGC-1α.

Sirtuins have been reported to positively regulate brown adipose tissue thermogenesis. Here the authors report that brown adipocytic SIRT7 suppresses whole-body energy expenditure and thermogenesis in mice, potentially by attenuating batokine gene expressions and Ucp1 mRNA translation.

Haematopoietic stem cells rely on glycolysis for their energy demands but whether this affects their fate is unknown. Here, the authors show that forcing the cells to rely on glycolysis is important for self-renewal and that this involves a reduction in mitochondrial mass.

This broad group of authors summarizes the impact of circadian factors on metabolic biology and offers recommendations on how to account for and report biological, environmental and experimental factors affecting circadian rhythms in metabolic studies in rodents.

Ryanodine receptor type 1 (RyR1) are involved in skeletal muscle contraction. Here, the authors show that a transient calcium leak in response to exercise-induced post translational modifications of RyR1 causes mitochondrial remodeling to improve respiration.