Aging & Longevity

Protein aggregation is a hallmark of age-related neurodegeneration. Yet, aggregation during normal aging and in tissues other than the brain is poorly understood. Here, we leverage the African turquoise killifish to systematically profile protein aggregates in seven tissues of an aging vertebrate. Age-dependent aggregation is strikingly tissue specific and not simply driven by protein expression differences. Experimental interrogation in killifish and yeast, combined with machine learning,...

The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical...

Perovskite solar cells promise to be part of the future portfolio of photovoltaic technologies, but their instability is slow down their commercialization. Major stability assessments have been recently achieved but reliable accelerated ageing tests on beyond small-area cells are still poor. Here, we report an industrial encapsulation process based on the lamination of highly viscoelastic semi-solid/highly viscous liquid adhesive atop the perovskite solar cells and modules. Our encapsulant...

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Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types...

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood...

Dysregulation of growth hormone (GH) signaling consistently leads to increased lifespan in laboratory rodents, yet the precise mechanisms driving this extension remain unclear. Understanding the molecular underpinnings of the beneficial effects associated with GH deficiency could unveil novel therapeutic targets for promoting healthy aging and longevity. In our pursuit of identifying metabolites implicated in aging, we conducted an unbiased lipidomic analysis of serum samples from growth...

The gut microbiome (GM) modulates body weight/composition and gastrointestinal functioning; therefore, approaches targeting resident gut microbes have attracted considerable interest. Intermittent fasting (IF) and protein pacing (P) regimens are effective in facilitating weight loss (WL) and enhancing body composition. However, the interrelationships between IF- and P-induced WL and the GM are unknown. The current randomized controlled study describes distinct fecal microbial and plasma...

The functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single-cell genomes from 19 human donors of increasing age, and discovered the heterogeneous mSV landscapes of hematopoietic stem and progenitor cells. While mSVs are continuously acquired throughout life, expanded subclones in our cohort are confined to individuals >60. Cells already harboring mSVs are more likely to acquire additional...

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Survival from UV-induced DNA lesions relies on nucleotide excision repair (NER) and the Mec1^(ATR) DNA damage response (DDR). We study DDR and NER in aging cells and find that old cells struggle to repair DNA and activate Mec1^(ATR). We employ pharmacological and genetic approaches to rescue DDR and NER during aging. Conditions activating Snf1^(AMPK) rescue DDR functionality, but not NER, while inhibition of the TORC1-Sch9^(S6K) axis restores NER and enhances DDR by tuning PP2A activity,...

As the most common degenerative joint disease, osteoarthritis (OA) contributes significantly to pain and disability during aging. Several genes of interest involved in articular cartilage damage in OA have been identified. However, the direct causes of OA are poorly understood. Evaluating the public human RNA-seq dataset showed that CBFB (subunit of a heterodimeric Cbfβ/Runx1, Runx2, or Runx3 complex) expression is decreased in the cartilage of patients with OA. Here, we found that the...

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disorder affecting the central nervous system. Evidence suggests that age-related neurodegeneration contributes to disability progression during the chronic stages of MS. Aging is characterized by decreased regeneration potential and impaired myelin repair in the brain. It is hypothesized that accelerated cellular aging contributes to the functional decline associated with neurodegenerative diseases. We assessed the impact of...

The selective removal of dysfunctional mitochondria, a process termed mitophagy, is critical for cellular health and impairments have been linked to aging, Parkinson disease, and other neurodegenerative conditions. A central mitophagy pathway is orchestrated by the ubiquitin (Ub) kinase PINK1 together with the E3 Ub ligase PRKN/Parkin. The decoration of damaged mitochondrial domains with phosphorylated Ub (p-S65-Ub) mediates their elimination though the autophagy system. As such p-S65-Ub has...

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Anti-aging research has made significant strides in identifying treatments capable of extending lifespan across a range of organisms, from simple invertebrates to mammals. This review showcases the current state of anti-aging interventions, highlighting the lifespan extensions observed in animal models through various treatments and the challenges encountered in translating these findings to humans. Despite promising results in lower organisms, the translation of anti-aging treatments to human...

Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA-approved medication for type II diabetes mellitus, has recently gained attention for its promising anti-aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI-1436),...

Each year, an estimated 7·7 million deaths are attributed to bacterial infections, of which 4.95 million are associated with drug-resistant pathogens, and 1·27 million are caused by bacterial pathogens resistant to the antibiotics available. Access to effective antibiotics when indicated prolongs life, reduces disability, reduces health-care expenses, and enables access to other life-saving medical innovations. Antimicrobial resistance undoes these benefits and is a major barrier to attainment...

Rising antimicrobial resistance (AMR) is a global health crisis for countries of all economic levels, alongside the broader challenge of access to antibiotics. As a result, development goals for child survival, healthy ageing, poverty reduction, and food security are at risk. Preserving antimicrobial effectiveness, a global public good, requires political will, targets, accountability frameworks, and funding. The upcoming second high-level meeting on AMR at the UN General Assembly (UNGA) in...

The decline of motor ability is a hallmark feature of aging and is accompanied by degeneration of motor synaptic terminals. Consistent with this, Drosophila motor synapses undergo characteristic age-dependent structural fragmentation co-incident with diminishing motor ability. Here, we show that motor synapse levels of Trio, an evolutionarily conserved guanine nucleotide exchange factor (GEF), decline with age. We demonstrate that increasing Trio expression in adult Drosophila can abrogate...