Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system.

Suppression of target of rapamycin complex 1 (TORC1) by rapamycin ameliorates aging in diverse species. S6 kinase (S6K) is an essential mediator, but the mechanisms involved are unclear. Here we show that activation of S6K specifically in Drosophila fat-body blocked extension of lifespan by rapamycin, induced accumulation of multilamellar lysosomes and blocked age-associated hyperactivation of the NF-κB-like immune deficiency (IMD) pathway, indicative of reduced inflammaging.

Intermittent rapamycin feeding recapitulates some effects of continuous treatment while maintaining lifespan extension.

Objective: Rapamycin, a powerful geroprotective drug, can have detrimental effects when administered chronically. We determined whether intermittent treatment of mice can reduce negative effects while maintaining benefits of chronic treatment.

Methods: From 6 months of age, male and female C3B6F1 hybrid mice were either continuously fed with 42 mg/kg rapamycin, or intermittently fed by alternating weekly feeding of 42 mg/kg rapamycin food with weekly control feeding.

Repeat length of C9orf72-associated glycine-alanine polypeptides affects their toxicity.

GC hexanucleotide repeat expansions in a non-coding region of the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). GC insertion length is variable, and patients can carry up to several thousand repeats. Dipeptide repeat proteins (DPRs) translated from GC transcripts are thought to be a main driver of toxicity.

Atlas of the aging mouse brain reveals white matter as vulnerable foci.

Aging is the key risk factor for cognitive decline, yet the molecular changes underlying brain aging remain poorly understood. Here, we conducted spatiotemporal RNA sequencing of the mouse brain, profiling 1,076 samples from 15 regions across 7 ages and 2 rejuvenation interventions. Our analysis identified a brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude.

Dietary restriction mitigates the age-associated decline in mouse B cell receptor repertoire diversity.

Aging impairs the capacity to respond to novel antigens, reducing immune protection against pathogens and vaccine efficacy. Dietary restriction (DR) extends life- and health span in diverse animals. However, little is known about the capacity of DR to combat the decline in immune function.

Toxicity of -associated dipeptide repeat peptides is modified by commonly used protein tags.

Hexanucleotide repeat expansions in the gene are the most prevalent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Transcripts of the expansions are translated into toxic dipeptide repeat (DPR) proteins. Most preclinical studies in cell and animal models have used protein-tagged polyDPR constructs to investigate DPR toxicity but the effects of tags on DPR toxicity have not been systematically explored.

Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy.

The licensed drug rapamycin has potential to be repurposed for geroprotection. A key challenge is to avoid adverse side effects from continuous dosing. Here we show that geroprotective effects of chronic rapamycin treatment can be obtained with a brief pulse of the drug in early adulthood in female Drosophila and mice.

Ageing-associated changes in transcriptional elongation influence longevity.

Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans.

Reduced insulin signaling in neurons induces sex-specific health benefits.

Reduced activity of insulin/insulin-like growth factor signaling (IIS) extends health and life span in mammals. Loss of the gene increases survival in mice and causes tissue-specific changes in gene expression. However, the tissues underlying IIS-mediated longevity are currently unknown.

The Role of GCN2 Kinase in Mediating the Effects of Amino Acids on Longevity and Feeding Behaviour in .

Restriction of amino acids in the diet can extend lifespan in diverse species ranging from flies to mammals. However, the role of individual amino acids and the underlying molecular mechanisms are only partially understood. The evolutionarily conserved serine/threonine kinase General Control Nonderepressible 2 (GCN2) is a key sensor of amino acid deficiency and has been implicated in the response of lifespan to dietary restriction (DR).

Regulation of the one carbon folate cycle as a shared metabolic signature of longevity.

The metabolome represents a complex network of biological events that reflects the physiologic state of the organism in health and disease. Additionally, specific metabolites and metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry to obtain the metabolomic profiles of canonical longevity pathways in C.

A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing.

Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally through eIF3-mediated translation.

Hormone-sensitive lipase couples intergenerational sterol metabolism to reproductive success.

Triacylglycerol (TG) and steryl ester (SE) lipid storage is a universal strategy to maintain organismal energy and membrane homeostasis. Cycles of building and mobilizing storage fat are fundamental in (re)distributing lipid substrates between tissues or to progress ontogenetic transitions. In this study, we show that Hormone-sensitive lipase (Hsl) specifically controls SE mobilization to initiate intergenerational sterol transfer in .

A neuronal blood marker is associated with mortality in old age.

Neurofilament light chain (NfL) has emerged as a promising blood biomarker for the progression of various neurological diseases. NfL is a structural protein of nerve cells, and elevated NfL levels in blood are thought to mirror damage to the nervous system. We find that plasma NfL levels increase in humans with age (n = 122; 21-107 years of age) and correlate with changes in other plasma proteins linked to neural pathways.

Sestrin is a key regulator of stem cell function and lifespan in response to dietary amino acids.

Dietary restriction (DR) promotes healthy aging in diverse species. Essential amino acids play a key role, but the molecular mechanisms are unknown. The evolutionarily conserved Sestrin protein, an inhibitor of activity of the target of rapamycin complex 1 (TORC1), has recently been discovered as a sensor of amino acids in vitro.

An Insulin-Sensitive Circular RNA that Regulates Lifespan in Drosophila.

Circular RNAs (circRNAs) are abundant and accumulate with age in neurons of diverse species. However, only few circRNAs have been functionally characterized, and their role during aging has not been addressed. Here, we use transcriptome profiling during aging and find that accumulation of circRNAs is slowed down in long-lived insulin mutant flies.

Glycine-alanine dipeptide repeats spread rapidly in a repeat length- and age-dependent manner in the fly brain.

Hexanucleotide repeat expansions of variable size in C9orf72 are the most prevalent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense transcripts of the expansions are translated by repeat-associated non-AUG translation into five dipeptide repeat proteins (DPRs). Of these, the polyGR, polyPR and, to a lesser extent, polyGA DPRs are neurotoxic, with polyGA the most abundantly detected DPR in patient tissue.

A nutritional memory effect counteracts benefits of dietary restriction in old mice.

Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at old age remains elusive. Here, we report results of a late-life DR switch experiment employing 800 mice, in which 24 months old female mice were switched from ad libitum (AL) to DR or vice versa.

Longevity in response to lowered insulin signaling requires glycine N-methyltransferase-dependent spermidine production.

Reduced insulin/IGF signaling (IIS) extends lifespan in multiple organisms. Different processes in different tissues mediate this lifespan extension, with a set of interplays that remain unclear. We here show that, in Drosophila, reduced IIS activity modulates methionine metabolism, through tissue-specific regulation of glycine N-methyltransferase (Gnmt), and that this regulation is required for full IIS-mediated longevity.

A triple drug combination targeting components of the nutrient-sensing network maximizes longevity.

Increasing life expectancy is causing the prevalence of age-related diseases to rise, and there is an urgent need for new strategies to improve health at older ages. Reduced activity of insulin/insulin-like growth factor signaling (IIS) and mechanistic target of rapamycin (mTOR) nutrient-sensing signaling network can extend lifespan and improve health during aging in diverse organisms. However, the extensive feedback in this network and adverse side effects of inhibition imply that simultaneous targeting of specific effectors in the network may most effectively combat the effects of aging.

Branched-Chain Amino Acids Have Equivalent Effects to Other Essential Amino Acids on Lifespan and Aging-Related Traits in Drosophila.

Branched-chain amino acids (BCAAs) have been suggested to be particularly potent activators of Target of Rapamycin (TOR) signaling. Moreover, increased circulating BCAAs are associated with higher risk of insulin resistance and diabetes in both mice and humans, and with increased mortality in mice. However, it remains unknown if BCAAs play a more prominent role in longevity than do other essential amino acids (EAAs).

Loss of miR-210 leads to progressive retinal degeneration in .

miRNAs are small, non-coding RNAs that regulate gene expression post-transcriptionally. We used small RNA sequencing to identify tissue-specific miRNAs in the adult brain, thorax, gut, and fat body of One of the most brain-specific miRNAs that we identified was miR-210, an evolutionarily highly conserved miRNA implicated in the regulation of hypoxia in mammals. In , we show that miR-210 is specifically expressed in sensory organs, including photoreceptors.