Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlated with lifespan extension, though it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (Htt) protein. Current management strategies temporarily relieve disease symptoms, but fail to affect the underlying disease progression. We previously demonstrated that calorie restriction ameliorated HD pathogenesis and slowed disease progression in HD mice1. We now report that overexpression of SIRT1, a mediator of beneficial metabolic effects of calorie restriction, protects neurons against mutant Htt toxicity, whereas reduction of SIRT1 exacerbates mutant Htt toxicity. Overexpression of SIRT1 significantly improves motor function, reduces brain atrophy, and attenuates mutant Htt-mediated metabolic abnormalities in both fragment and full-length HD mouse models. Further mechanistic studies suggest that SIRT1 prevents mutant Htt-induced decline in BDNF levels and its receptor Trk-B signaling, and restores medium spiny neuronal DARPP32 levels in the striatum. SIRT1 deacetylase activity is required for SIRT1-mediated neuroprotection in HD models. Notably, we demonstrate that mutant Htt interacts with SIRT1 and inhibits SIRT1 deacetylase activity. Inhibition of SIRT1 deacetylase activity results in hyperacetylation of SIRT1 substrates such as FOXO3a thereby inhibiting its prosurvival function. Overexpression of SIRT1 counteracts mutant Htt-induced deacetylase deficit, enhances deacetylation of FOXO3a, and facilitates cell survival. These findings demonstrate a neuroprotective role of SIRT1 in mammalian HD models, indicate key mediators of this protection, and open new avenues for the development of neuroprotective strategies in HD.

Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistance. However, the mechanisms underlying obesity-induced inflammation remain elusive. Here we show that obesity promotes mtDNA release into the cytosol, where it triggers inflammatory responses by activating the DNA-sensing cGAS-cGAMP-STING pathway. Fat-specific knockout of disulfide-bond A oxidoreductase-like protein (DsbA-L), a chaperone-like protein originally identified in the mitochondrial matrix, impaired mitochondrial function and promoted mtDNA release, leading to activation of the cGAS-cGAMP-STING pathway and inflammatory responses. Conversely, fat-specific overexpression of DsbA-L protected mice against high-fat diet-induced activation of the cGAS-cGAMP-STING pathway and inflammation. Taken together, we identify DsbA-L as a key molecule that maintains mitochondrial integrity. DsbA-L deficiency promotes inflammation and insulin resistance by activating the cGAS-cGAMP-STING pathway. Our study also reveals that, in addition to its well-characterized roles in innate immune surveillance, the cGAS-cGAMP-STING pathway plays an important role in mediating obesity-induced metabolic dysfunction.

Alzheimer’s disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and ‘eumetabolic’ activities may possess superior efficacies compared to less pluripotent remedies.