Aging & Longevity

Aging-associated vulnerability to coronavirus disease 2019 (COVID-19) remains poorly understood. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected aged mice lacking SIRT2, a cytosolic NAD^(+)-dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD^(+) booster, 78c, protects aged mice from lethal infection. Mechanistically, we demonstrate that SIRT2 modulates the acetylation of cyclic GMP-AMP synthase...

Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regression of liver metastases. Mechanistically, in vivo armed macrophages expand tumor reactive CD8^(+) T cells, which acquire features of progenitor exhausted T cells and kill cancer cells independently of CD4^(+) T...

CD8^(+) T cells that are repeatedly exposed to antigenic stimulation, such as in the context of progressing neoplasms and chronic viral infections, acquire a dysfunctional or hypofunctional state that is generally known as exhaustion. There have been considerable efforts to develop therapeutic strategies that prevent exhaustion in these pathological scenarios, but there has been limited success. This may be because exhaustion is not the only source of T cell hypofunction in cancer and chronic...

Fibroblasts form a major component of the stroma in normal mammary tissue and breast tumors. Here, we have applied longitudinal single-cell transcriptome profiling of >45,000 fibroblasts in the mouse mammary gland across five different developmental stages and during oncogenesis. In the normal gland, diverse stromal populations were resolved, including lobular-like fibroblasts, committed preadipocytes and adipogenesis-regulatory, as well as cycling fibroblasts in puberty and pregnancy. These...

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Sex disparities have been epidemiologically demonstrated in non-reproductive cancers, yet how the sex-specific intrinsic microbiome orchestrates the immune system to affect these disparities is unclear. Here we identify a subpopulation of RETNLG^(+)LCN2^(+) senescence-like neutrophils (RLSNs) that preferentially accumulate in the male tumor microenvironment and exert a strong immunosuppressive effect to limit antitumor immunity, resulting in poor prognosis for patients with bladder cancer. This...

Clinical and genetic research links altered cholesterol metabolism with ALS development and progression, yet pinpointing specific pathomechanisms remain challenging. We investigated how cholesterol dysmetabolism interacts with protein aggregation, demyelination, and neuronal loss in ALS. Bulk RNAseq transcriptomics showed decreased cholesterol biosynthesis and increased cholesterol export in ALS mouse models (GA-Nes, GA-Camk2a GA-CFP, rNLS8) and patient samples (spinal cord), suggesting an...

Differentiating sequencing errors from true variants is a central genomics challenge, calling for error suppression strategies that balance costs and sensitivity. For example, circulating cell-free DNA (ccfDNA) sequencing for cancer monitoring is limited by sparsity of circulating tumor DNA, abundance of genomic material in samples and preanalytical error rates. Whole-genome sequencing (WGS) can overcome the low abundance of ccfDNA by integrating signals across the mutation landscape, but higher...

CONCLUSION: The core category,'Seniors on the margin of digital health literacy,'was selected to encompass the other seven categories.

CONCLUSION: This study identified the primary facilitators and barriers to community-based cognitive impairment management within the context of current policies. To enhance the effectiveness of interventions, policymakers, health departments, and community organizations should actively address the identified barriers and leverage the facilitators. Additionally, the findings provide valuable insights for other countries facing similar challenges in cognitive impairment management. Future...

In Arabidopsis, late endosome-localized ABNORMAL SHOOT 3 (ABS3) promotes senescence through a direct interaction with AUTOPHAGY8 (ATG8). However, the molecular mechanisms underlying the regulation of the ABS3-mediated senescence pathway are not well understood. Here, we report that HOOKLESS 1 (HLS1) acts as a negative regulator of plant senescence and the ABS3-mediated senescence pathway. We identify the localizations of HLS1 at the plasma membrane and endosomes in addition to the nucleus....

Telomere length regulation is essential for genome stability as short telomeres can trigger cellular senescence and apoptosis constituting an integral aspect of biological aging. Telomere biology disorders (TBDs) such as dyskeratosis congenita (DC) are rare, inherited diseases with known mutations in at least 16 different genes encoding components of the telomere maintenance complexes. The precise role of TEN1, part of the CST complex (CTC1, STN1, and TEN1), and the consequences of its loss of...

Preserving hematopoietic stem cell (HSC) functionality is essential for maintaining healthy blood and the immune system throughout life. HSC function declines with age; however, the underlying mechanisms are not fully understood. Using an inducible mosaic mouse model to overexpress the transcription factor Bcl11a in the hematopoietic compartment, we found that an aging-related increase in Bcl11a mitigated HSC functional decline, promoted IL-1β production in the bone marrow (BM), and accelerated...

BACKGROUND: As individuals experience age-related changes, such as cognitive decline or hospitalizations, their ability to live independently at home may be impacted. Decision-making and planning are essential in order to support successful aging-in-place (AIP), which is defined as continuing to live in one's home and community. Despite making plans at one single time-point, prior research has demonstrated that decision-making among older adults is not stagnant.

Vascular contributions to cognitive impairment and dementia (VCID) represent a major public health challenge in the aging population, with age-related cerebromicrovascular dysfunction playing a critical role in its development. Understanding the mechanisms underlying cerebromicrovascular aging is crucial for devising strategies to mitigate this burden. Among the key hallmarks of aging, genomic instability and genetic heterogeneity have emerged as significant drivers of age-related diseases....

Sleep disorders, particularly insomnia and obstructive sleep apnea, are increasingly implicated as significant contributors to cognitive decline, dementia, and neurodegenerative diseases such as Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID). However, the extent and specificity of these associations remain uncertain. This meta-analysis evaluates the impact of common sleep disorders on the risk of developing dementia and cognitive decline. A comprehensive search of...

CONCLUSIONS: Loneliness and social isolation among community-dwelling older adults are complex issues with profound implications for physical, mental, and social well-being. Addressing these challenges requires integrative approaches that consider individual, relational, and contextual factors. Further longitudinal and standardized research is needed to improve our understanding of the long-term impacts and effectiveness of interventions to mitigate these issues.

CONCLUSIONS: This study utilized a relatively large and highly representative sample of community-dwelling residents to identify factors associated with fractures in independent older adults. Even in independent older adults who were not certified as requiring long-term care, fractures were significantly associated with a decline in multiple health domains. These findings provide valuable insights that can inform efforts to promote healthy aging and reduce care dependency.

Social factors influence health outcomes and life expectancy. Individuals living in poverty often have adverse health outcomes related to chronic inflammation that affect the cardiovascular, renal, and pulmonary systems. Negative psychosocial experiences are associated with transcriptional changes in genes associated with complex traits. However, the underlying molecular mechanisms by which poverty increases the risk of disease and health disparities are still not fully understood. To bridge the...

Identifying factors affecting lifespan, including genes or proteins, enables effective interventions. We prioritized potential drug targets and provided insights into biological pathways for healthy longevity by integrating Mendelian randomization, cohort, and experimental studies. We identified causal effects of tissue-specific genetic transcripts and serum protein levels on three longevity outcomes: the parental lifespan, the top 1% and 10% extreme longevity, utilizing Mendelian randomization...