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Variants in GBA1 resulting in decreased lysosomal glucocerebrosidase (GCase) activity are a common risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Incomplete penetrance of GBA1 variants suggests that additional genes contribute to PD and DLB manifestation. By using a pooled genome-wide CRISPR interference screen, we identified copper metabolism MURR1 domain-containing 3 (COMMD3) protein, a component of the COMMD/coiled-coil domain-containing protein 22...

The Atg8-family proteins, including LC3B (microtubule-associated protein 1 light chain 3 beta), are pivotal for key steps in the autophagy process. Proper regulation of LC3B homeostasis is essential for its function. Although LC3B is modulated by various posttranslational modifications (PTMs), the impact of these modifications on LC3B protein homeostasis remains unclear. Neddylation, a recently identified ubiquitin-like modification, plays diverse biological roles. Here, we identify LC3B as a...

Genetic effects on complex traits may depend on context, such as age, sex, environmental exposures, or social settings. However, it remains often unclear if the extent of context dependency, or gene-by-environment interaction (GxE), merits more involved models than the additive model typically used to analyze data from genome-wide association studies (GWAS). Here, we suggest considering the utility of GxE models in GWAS as a trade-off between bias and variance parameters. In particular, we...

The present paper provides the first integrated assessment of the capacity of the flavonol, fisetin, to induce hormetic dose responses. Fisetin was shown to induce hormetic dose responses in cellular and in vivo animal model systems affecting a broad range of endpoints of potential therapeutic and public health significance across the entire lifespan. Fisetin was effective in slowing aging processes, acting as a senolytic agent in multiple organ systems, in an hormetic fashion. In addition,...

Spermidine is a naturally occurring polyamine present in all cells and is necessary for viability in eukaryotic cells. The cellular levels of spermidine decline as an organism ages, and its supplementation has been found to extend lifespan in yeast, worms, flies, mice, and human cultured cells. The lifespan extending effect of spermidine is thought to be due to its ability to induce autophagy, a turnover of cellular components. Mitochondrial dysfunction is believed to be a major driver of the...

Chaperone-mediated autophagy (CMA) is a selective autophagic pathway that targets specific proteins for lysosomal degradation, playing a crucial role in maintaining cellular homeostasis. Recent research has highlighted the involvement of CMA in aging and age-related diseases, yet its regulation remains complex. The study by Khawaja et al. provides novel insights into the sex-specific and cell-type-specific regulation of CMA during aging. This commentary discusses the key findings of this study,...

ObjectiveWe compared pain prevalence and intensity between caregivers and non-caregivers, as well as between different types of caregivers.MethodUsing two rounds of data from the National Social Life, Health, and Aging Project, we used regression models to analyze differences in pain prevalence and intensity between caregivers and non-caregivers at baseline (2010-2011) and follow-up (2015-2016). The sample consisted of 2332 participants aged 62 and older (352 caregivers and 1980...

Science, Volume 388, Issue 6743, April 2025.

Science, Volume 388, Issue 6743, April 2025.

Science, Volume 388, Issue 6743, April 2025.