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The heart relies on fatty acid oxidation as its main energy source. Here they show that impaired fatty acid metabolism disrupts mitophagy in the heart and that enhancing mitophagy via USP30 inhibition can restore heart function in models of fatty acid oxidation deficiency.

Toren Finkel lauds two books outlining very different ways of achieving a longer ‘healthspan’ — through pharmacology or integrative care.

Here it is shown that the NAD-dependent deacetylase SIRT2 is an essential component of necrosis, and that mouse hearts that do not contain SIRT2 or that are treated with a pharmacological inhibitor of SIRT2 are largely protected from ischaemic injury.

Countering the effects of Bacillus anthracis lethal toxin proteolytic activity with a growth factor cocktail reactivates ERK, prevents cytotoxicity and promotes survival of B. anthracis-infected mice.

In the process of autophagy, cellular constituents are degraded and recycled. Toren Finkel and his colleagues show that this process also regulates the secretion of a key blood-clotting protein by endothelial cells, such that transient inhibition of autophagy might be therapeutically useful for treating thrombotic disorders.

Until the recent discovery of the mitochondrial calcium uniporter (MCU), the effect of increases in mitochondrial calcium levels could not be tested in vivo. Finkel and colleagues have knocked out the gene coding for MCU in adult mice, and show that MCU is required for transport of calcium into the mitochondria. They also show that, in its absence, the function of skeletal muscle is altered; however, surprisingly, no effects are observed on the sensitivity to cell-death-inducing agents.

Lysosomes maintain RPE health via TFEB/E3-regulated autophagy. Here, the authors show deregulated AKT2/SIRT5/TFEB signaling in the RPE inhibits both lysosomal and mitochondrial function and leads to AMD, suggesting this pathway might provide a therapeutic target for AMD.

Toren Finkel reviews how metabolism and aging are connected, and highlights pathways that could be pharmacologically targeted to combat aging and age-related disease.

A mitochondrial protein may mediate a dangerous side-effect of some recreational drugs.

Although they are damaging when produced in large quantities, low levels of reactive oxygen species (ROS) can function within specific signalling pathways, based on the reversible oxidation of crucial Cys residues in reduction–oxidation (redox)-sensitive target proteins. Understanding these pathways has implications for metabolic regulation, innate immunity, stem cell biology, tumorigenesis and ageing.

It is often difficult to identify functional SNPs from disease-associated SNPs in linkage disequilibrium. Here, the authors present Reel-seq, SDCP-MS and AIDP-Wb, three sequential methodologies for fSNP identification and characterization.

The serine protease TMPRSS2 primes SARS-CoV-2 glycoprotein for cell entry. Here, the authors perform a screen to identify drugs that reduce TMPRSS2 expression and find that halofuginone modulates proteasome-mediated degradation of TMPRSS2 and reduces entry of SARS-CoV-2.

Beta3-adrenergic receptor signaling regulates adipose tissue browning. Here, the authors show that barr2 regulates internalization of beta3-adrenergic receptors and that mice lacking barr2 in adipocytes are protected from diet-induced weight gain and metabolic complications.

Lysosomal membrane damage triggers a lipid signalling pathway that repairs lysosomes via lipid transport at newly established endoplasmic reticulum–lysosomal membrane contact sites.

The molecular mechanisms that regulate senescence are incompletely understood. Here the authors couple high-throughput mapping of disease-associated functional SNPs (fSNPs) with proteomics analysis of fSNP-binding proteins to identify the transcription factor CUX1 as an activator of p16 expression and a regulator of senescence.

E3 ligase subunit protein Fbxo48 interacts with phosphorylated Ampkα and mediates its proteasomal degradation. Interruption of the pAmpkα/Fbxo48 interaction by a small-molecule BC1618 promoted Ampkα activation and improved insulin sensitivity.

Permeabilization of the mitochondria usually leads to caspase activation and apoptosis. In the absence of caspase activation, these same mitochondrial changes can also lead to cell death. A recent study suggests that when good mitochondria go bad, the activation of both glycolysis and autophagy may permit cellular survival.

Zhao et al. find that AMPK phosphorylates and activates the mitochondrial Ca²⁺ uniporter in response to low energy status in mitosis, allowing Ca²⁺ entry into mitochondria to boost mitochondrial respiration.

The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer. Now, Shuklaet al.demonstrate that mice lacking BRCA1 in cardiomyocytes are more sensitive to ischaemia than control mice, and that BRCA1 is elevated in human tissues exposed to ischaemia, suggesting a cardioprotective role for BRCA1.

Mice deficient in the Polycomb repressor Bmi1 have a shortened lifespan and develop numerous abnormalities including defects in stem cell self-renewal and thymocyte maturation. Here it is demonstrated that cells derived from Bmi1^−/− mice also show a marked elevation in the intracellular levels of reactive oxygen species, corresponding to the derepression of previously identified Polycomb target genes and sufficient to engage the DNA damage response pathway.

Cell-type-specific anthrax toxin receptor CMG2-null mice are generated and used to show that the Bacillus anthracis toxins lethal toxin (LT) and oedema toxin (ET) target distinct cell types; in contrast to previous suggestions, it is shown that endothelial cells are not key targets for either toxin and instead LT targets cardiomyocytes and vascular smooth muscle cells whereas ET targets hepatocytes.

Certain oncogenes seem to be able to trigger cellular senescence and growth arrest, thereby holding cancer at bay. Two new studies suggest that oncogenes trigger senescence through activation of a pathway initially described as sensing DNA damage.

Mitochondria supply cells with energy, but in the process produce potentially damaging oxidants. It seems that a protein required to produce new mitochondria also protects against the resulting oxidative damage.

Reducing food intake increases lifespan in many species. A small molecule that occurs naturally in plants seems to mimic the beneficial effects of caloric restriction and extend longevity in yeast.

Intracellular oxidants may contribute to overall lifespan, in part by affecting stem cells. The connection between oxidants and aging now gains strength in a study of hematopoietic stem cells, which respond to oxidants by activating a pathway leading to stem cell exhaustion (pages 446–451).

Sirtuins are highly conserved enzymes with key roles in life extension in multiple organisms. A study now describes selective autophagic degradation of nuclear SIRT1 in senescent cells. These observations suggest that blocking sirtuin degradation could be a potential approach for anti-ageing therapies.

What determines how long we will live? Studies of simple organisms, single cells and mammals hint that certain shared principles underlie ageing, and raise the possibility of devising ways to extend life — if we want to.

Reactive oxygen species (ROS) have important roles in health and disease, but are chemically complex and difficult to measure accurately. This consensus statement proposes guidelines and best practices on the nomenclature and assessment of ROS, oxidative reactions and oxidative damage in cells, tissues and in vivo.

This Perspective lays out the impetus and goals of the Cellular Senescence Network established to comprehensively identify and characterize senescent cells (SnCs) across tissues and lifespan, providing a publicly available SnC atlas.

Sun et al. describe how to image and quantify mitophagy in both living cells and tissues, using the pH-sensitive fluorescent reporter mt-Keima. This protocol provides information for analysis by both confocal and super-resolution microscopy.