Aging & Longevity

Dynamically organized chromatin complexes often involve multiplex chromatin interactions and sometimes chromatin-associated RNA^(1-3). Chromatin complex compositions change during cellular differentiation and ageing, and are expected to be highly heterogeneous among terminally differentiated single cells^(4-7). Here we introduce the multinucleic acid interaction mapping in single cells (MUSIC) technique for concurrent profiling of multiplex chromatin interactions, gene expression and...

Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies^(1,2). Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena³. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune...

Lysosomes are degradation and signalling centres crucial for homeostasis, development and ageing¹. To meet diverse cellular demands, lysosomes remodel their morphology and function through constant fusion and fission^(2,3). Little is known about the molecular basis of fission. Here we identify HPO-27, a conserved HEAT repeat protein, as a lysosome scission factor in Caenorhabditis elegans. Loss of HPO-27 impairs lysosome fission and leads to an excessive tubular network that ultimately...

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Telomere dysfunction is intricately linked to the aging process and stands out as a prominent cancer hallmark. Here we demonstrate that telomerase activity is differentially regulated in cancer and normal cells depending on the expression status of fructose-1,6-bisphosphatase 1 (FBP1). In FBP1-expressing cells, FBP1 directly interacts with and dephosphorylates telomerase reverse transcriptase (TERT) at Ser227. Dephosphorylated TERT fails to translocate into the nucleus, leading to the inhibition...

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated...

Sarcopenia is a major contributor to disability in older adults, and thus, it is key to elucidate the mechanisms underlying its development. Increasing evidence suggests that impaired macroautophagy/autophagy contributes to the development of sarcopenia. However, the mechanisms leading to reduced autophagy during aging remain largely unexplored, and whether autophagy activation protects from sarcopenia has not been fully addressed. Here we show that the autophagy regulator TP53INP2/TRP53INP2 is...

Apoptosis signal-regulating kinase 1 (ASK1) is a crucial stress sensor, directing cells toward apoptosis, differentiation, and senescence via the p38 and JNK signaling pathways. ASK1 dysregulation has been associated with cancer and inflammatory, cardiovascular, and neurodegenerative diseases, among others. However, our limited knowledge of the underlying structural mechanism of ASK1 regulation hampers our ability to target this member of the MAP3K protein family towards developing therapeutic...

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To preserve germination ability, plant seeds must be protected from environmental stresses during the storage period. Here, we demonstrate that autophagy, an intracellular degradation system, maintains seed germination ability in Arabidopsis thaliana. The germination ability of long-term (>5 years) stored dry seeds of autophagy-defective (atg) mutant and wild-type (WT) plants was compared. Long-term stored (old) seeds of atg mutants showed lower germination ability than WT seeds, although...

Fire suppression is the primary management response to wildfires in many areas globally. By removing less-extreme wildfires, this approach ensures that remaining wildfires burn under more extreme conditions. Here, we term this the "suppression bias" and use a simulation model to highlight how this bias fundamentally impacts wildfire activity, independent of fuel accumulation and climate change. We illustrate how attempting to suppress all wildfires necessarily means that fires will burn with...

Aging populations are susceptible to heat-related mortality because of physiological factors and comorbidities. However, the understanding of individual vulnerabilities in the aging population is incomplete. In the Chinese Longitudinal Healthy Longevity Survey, we assessed daily heatwave exposure individually for 13,527 participants (median age = 89 years) and 3,249 summer mortalities during follow-up from 2008 to 2018. The mortality risk during heatwave days according to relative temperature is...

Classical genetic analysis is invaluable for understanding the genetic interactions underlying specific phenotypes, but requires laborious and subjective experiments to characterize polygenic and quantitative traits. Contrarily, transcriptomic analysis enables the simultaneous and objective identification of multiple genes whose expression changes are associated with specific phenotypes. Here, we conducted transcriptomic analysis of genes crucial for longevity using datasets with...

Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female...

A major consequence of aging and stress, in yeast to humans, is an increased accumulation of protein aggregates at distinct sites within the cells. Using genetic screens, immunoelectron microscopy, and three-dimensional modeling in our efforts to elucidate the importance of aggregate annexation, we found that most aggregates in yeast accumulate near the surface of mitochondria. Further, we show that virus-like particles (VLPs), which are part of the retrotransposition cycle of Ty elements, are...

The complex biological mechanisms underlying human brain aging remain incompletely understood. This study investigated the genetic architecture of three brain age gaps (BAG) derived from gray matter volume (GM-BAG), white matter microstructure (WM-BAG), and functional connectivity (FC-BAG). We identified sixteen genomic loci that reached genome-wide significance (P-value < 5×10^(-8)). A gene-drug-disease network highlighted genes linked to GM-BAG for treating neurodegenerative and...

TFEB and TFE3 belong to the MiT/TFE family of transcription factors that bind identical DNA responsive elements in the regulatory regions of target genes. They are involved in regulating lysosomal biogenesis, function, exocytosis, autophagy, and lipid catabolism. Precise control of TFEB and TFE3 activity is crucial for processes such as senescence, stress response, energy metabolism, and cellular catabolism. Dysregulation of these factors is implicated in various diseases, thus researchers have...

Aging is characterized by a decline in physical and cognitive functions, often resulting in decreased quality of life. Physical activity has been suggested to potentially slow down various aspects of the aging process, a theory that has been supported by studies of Masters Athletes (MA). For example, MA usually have better cognitive and physical functions than age-matched sedentary and healthy older adults (OA), making them a valuable model to gain insights into mechanisms that promote physical...