Volume 3 Issue 2, February 2023

Zhang and colleagues demonstrate how the premature aging phenotypes in progeria involve a mitotic spindle-assembly-checkpoint protein, BUBR1. BUBR1 is misanchored to the nuclear membrane by progerin and its mRNA is destabilized in progeria, preventing it from functioning properly.

Aging is known to be associated with a decline in memory and mood, but the molecular mechanisms that underlie these changes remain unclear. Moigneu, Abdellaoui and colleagues show that growth differentiation factor 11 reverses deficits in these functions in aged mice, pointing the way towards a novel pro-mnemonic and antidepressant therapeutic target.

Mitochondrial dysfunction is central in biological aging, but experimentally controlling mitochondria in vivo to test causality has been difficult. Optogenetically preserving mitochondrial function with age addressed this difficulty and increased lifespan and healthspan in Caenorhabditis elegans.

Age-related decline in brain health is associated with poor blood flow and limitations in energy supply, although the vascular mechanisms are poorly understood. We report an age-related decrease in responsivity of brain microvessels, accompanied by a decrease in vessel density and loss of vascular mural cell processes.

Neuroinflammation is increasingly recognized as an important pathological trigger for the development and progression of Alzheimer’s disease. However, the molecular mechanism remains largely unclear. We identify activation of the neuroimmune cGAS–STING signaling pathway as a critical molecular link, predominantly in microglia, that contributes to Alzheimer’s disease pathogenesis.

Using light to optogenetically power mitochondria, this study shows that opposing the age-related decline in mitochondrial membrane potential leads to increased healthspan and lifespan in Caenorhabditis elegans. This result points to mitochondrial charge as a fundamental regulator of biological aging.

Dietary supplementation of the clinical PI3K inhibitor alpelisib (Piqray) extends the lifespan of male and female mice and is associated with greater strength and balance but reduced bone mass and mild hyperglycaemia.

Frailty of the aged brain may relate to impaired vascular control and limitations in energy supply. The authors report an age-related decrease in responsivity of brain microvessels, accompanied by a decrease in vessel density and loss of vascular mural cell processes.

Zhang et al. demonstrate that targeting BUBR1, a nuclear mitotic spindle assembly checkpoint protein, alleviates premature aging phenotypes of progeria in mice via disrupting its nuclear mislocalization induced by progerin interaction.

Xie et al. identify activation of the innate immune cGAS-STING pathway in human Alzheimer’s disease (AD) brain and 5×FAD mouse model of AD. Suppressing the cGAS-STING pathway is shown as a target to alleviate AD-associated pathogenesis in mice.

Moigneu, Abdellaoui and colleagues show that GDF11 attenuates depression-like behavior and improves memory in aged mice through neuronal autophagy and mTOR. Serum levels of GDF11 are inversely associated with depression in patients.

Dobyns et al. use latent variable modeling to derive a single, putative measure of resilience that buffered the effects of the hallmark Alzheimer’s disease pathologies, tau and amyloid, on episodic memory and non-memory decline, respectively.