Aging & Longevity

Big data approaches to discovering nongenetic risk factors have lagged behind genome-wide association studies that routinely uncover novel genetic risk factors for diverse diseases. Instead, epidemiology typically focuses on candidate risk factors. Since modern biobanks contain thousands of potential risk factors, candidate approaches may introduce bias, inadequately control for multiple testing, and overlook important signals. Doublethink, a model-averaged hypothesis testing approach, offers a...

Impaired neural stem cell (NSC) proliferation/activation is associated with brain aging, but the underlying mechanisms remain poorly understood. Here, we unexpectedly find that DMTF1, a transcription factor that regulates the Arf/p53 axis in cancer, is down-regulated in the NSCs of a premature aging model driven by telomerase deficiency. DMTF1 up-regulation was able to rescue the impaired proliferation of telomere dysfunctional NSCs. Mechanistically, DMTF1 regulates the transcription of Arid2...

Aging involves widespread metabolic dysregulation, including a decline in total nicotinamide adenine dinucleotide (NAD) levels. While NAD precursor supplementation elevates total NAD levels, it does not reveal tissue-specific effects of an altered NADH [reduced form of NAD^(+) (oxidized NAD)]/NAD^(+) balance. To address this, we generated transgenic Drosophila expressing the genetically encoded xenotopic enzyme LbNOX, which converts NADH to NAD^(+). LbNOX expression modulated both NAD(H) and...

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Aging is characterized by systemic inflammation and progressive cognitive decline, yet the molecular pathways linking peripheral aging signals to central nervous system dysfunction remain elusive. Here, we identify plasma extracellular vesicle (EV)-derived long interspersed nuclear element-1 (LINE-1) RNA as a potent systemic aging factor mediating neuroinflammation and cognitive impairment in humans and mice. Plasma EV LINE-1 RNA levels markedly increase with age and strongly correlate with...

Regulated cell death (RCD) shapes neoplastic transformation, tumor progression, and response to treatment. While apoptosis was long viewed as the only RCD variant, additional modalities, including necroptosis, pyroptosis, and ferroptosis, have been characterized. These interconnected pathways operate in a context-dependent manner to influence the dynamic interplay between malignant and non-malignant cells that governs disease progression or regression, both naturally and during therapy. Major...

Age-related muscle dysfunction is a major contributor to disability, frailty, and poor clinical outcomes in older adults. Skeletal Muscle Function Deficit (SMFD) framework integrates multiple domains as: muscle mass, muscle density, strength, and power to capture a broader spectrum of age-related muscle dysfunction. The primary aims of these analyses are to develop and validate a composite SMFD score and evaluate its association with key geriatric outcome. This study used data from the InCHIANTI...

Myocytes are exceptionally long-lived cells that must maintain proteome integrity over decades while adjusting for changes in functional output and metabolic demand. We used in vivo stable isotope labeling combined with mass spectrometry proteomics and correlated multi-isotope imaging mass spectrometry to quantify and visualize protein turnover across cardiac, fast-twitch, and slow-twitch skeletal muscles, creating a resource of hundreds of individual protein turnover rates from each tissue. We...

Cells terminally arrested in the cell cycle that exhibit a distinct secretory phenotype are referred to as senescent. These cells play a complex role during tumor progression; they can inhibit or promote tumor growth depending on disease stage. We developed a mouse model that allows monitoring and selective elimination of cells expressing high levels of the cyclin-dependent kinase inhibitor p16 and interleukin-6. These mice, termed SuSe (suicidal senescence), were crossed with the mouse mammary...

CONCLUSION: Adherence to a healthy diet may contribute to reducing the premature aging risk in adult survivors of childhood cancer. Interventions that support healthy eating in this population could potentially have benefits for long-term health outcomes.

Defective nucleocytoplasmic transport (NCT) has emerged as a contributing factor in the pathogenesis of neurodegenerative diseases and aging. Valosin-containing protein (VCP) is an AAA+ATPase required for disassembly of protein complexes, and mutations in VCP cause neurodegenerative and neuromuscular diseases. We find that VCP is required for quality control of nuclear pore complexes (NPCs) by extracting selected nucleoporins from NPCs for proteasome-mediated degradation. Pathogenic VCP variants...

CONCLUSION: Our findings suggest a bidirectional relationship between MetS and EAA, with biological aging potentially mediating metabolic deterioration. EAA may serve as both a marker and mediator of metabolic health, and a promising target for prevention and intervention.

Insulin action on the skeleton is essential for bone development and whole-body energy metabolism, however a global view of signaling in this tissue is lacking. Furthermore, whether there are signaling differences that drive the gene-specific activation under insulin-resistant (IR) or ageing conditions is unknown. Here, we perform a phosphoproteomic analysis of insulin signaling in the bones of young, lean, insulin-sensitive versus old, obese, IR mice revealing a rewiring of phosphorylation. We...

Anopheles gambiae is one of the principal vectors of human malaria. Over the past two decades, transgenic mosquito strains have been essential tools for studying mosquito biology and developing genetic control strategies such as gene drives. Mosquito transformants are typically identified using fluorescent markers, which are assumed to be phenotypically neutral. While generating CRISPR-based gene drive strains carrying an OpIE2-DsRed marker we unexpectedly found that transgenic females were...

CONCLUSIONS: ε4 contributes to literacy decline among older adults, presumably due in part to the accumulation of neuropathologies associated with ε4. We discuss the potential clinical implications of ε4-related literacy decline.

CONCLUSIONS: A decision support tool for caregivers of PLwD that provides education about transitions in care site, along with support for the emotional aspects of decision making, is highly acceptable and supports caregivers' ability to engage with what can be a challenging topic.

CONCLUSIONS: In the Rugao Aging Cohort, significant gender differences of thickness of all macular layers between males and females were identified, with males exhibiting thicker inner rings and thinner outer rings compared to females. Notably, cognitive decline was associated with the thinning of the central part and inner ring of macula exclusively in females. These results suggest that when macular thickness is used as a risk marker for cognitive decline, its gender bias should be carefully...

Memory functions are susceptible to age-related cognitive decline, making it essential to explore the underlying neurophysiological mechanisms that contribute to memory function during healthy ageing. Resting-state EEG (rsEEG) parameters, particularly the aperiodic exponent, a marker of cortical excitation-inhibition balance, and individual alpha peak frequency, a correlate of neural processing efficiency, have demonstrated associations with ageing and cognitive functions. This study...

Aging is a progressive process characterized by cellular and molecular damage leading to mitochondrial dysfunction and cognitive decline. Mitochondrial dysfunction is a critical factor in memory impairment in aging and neurodegenerative diseases. While sex differences in aging have been observed across various species, the underlying cellular and molecular mechanisms remain poorly understood, mainly focused on mitochondrial proteostasis. This study examined hippocampal-dependent cognitive...

CONCLUSIONS: The population of nonagenarians was specific in causes of death and comorbidities. Improving end-of-life care for these patients can include a high access to specialist palliative care and symptoms management.