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Diabetes & Metabolic Syndrome May 2024Although the life expectancy of women systematically and robustly exceeds that of men, specific differences and molecular mechanisms of sex in influencing longevity...
BACKGROUND AND AIMS
Although the life expectancy of women systematically and robustly exceeds that of men, specific differences and molecular mechanisms of sex in influencing longevity phenotypes remain largely unknown. Therefore, we performed transcriptome sequencing of peripheral blood samples to explore regulatory mechanisms of healthy longevity by incorporating sex data.
METHODS
We selected 34 exceptional longevity (age: 98.26 ± 2.45 years) and 16 controls (age: 52.81 ± 9.78) without advanced outcomes from 1363 longevity and 692 controls recruited from Nanning of Guangxi for RNA sequencing 1. The transcriptome sequencing 1 data of 50 samples were compared by longevity and sex to screen differentially expressed genes (DEGs). Then, 121 aging samples (40-110 years old) without advanced outcomes from 355 longevity and 294 controls recruited from Dongxing of Guangxi were selected for RNA sequencing 2. The genes associated with aging from the transcriptome sequencing 2 of 121 aging samples were filtered out. Finally, the gender-related longevity candidate genes and their possible metabolic pathways were verified by cell model of aging and a real-time polymerase chain reaction (RT-PCR).
RESULTS
Metabolism differs between male and female and plays a key role in longevity. Moreover, the principal findings of this study revealed a novel key gene, UGT2B11, that plays an important role in regulating lipid metabolism through the peroxisome proliferator activated receptor gamma (PPARG) signalling pathway and ultimately improving lifespan, particularly in females.
CONCLUSION
The findings suggest specific differences in metabolism affecting exceptional longevity phenotypes between the sexes and offer novel therapeutic targets to extend lifespan by regulating lipid homeostasis.
PubMed: 38762968
DOI: 10.1016/j.dsx.2024.103039 -
Aging May 2024
PubMed: 38761173
DOI: 10.18632/aging.205918 -
Molecular Cancer May 2024Aging and cancer exhibit apparent links that we will examine in this review. The null hypothesis that aging and cancer coincide because both are driven by time,... (Review)
Review
Aging and cancer exhibit apparent links that we will examine in this review. The null hypothesis that aging and cancer coincide because both are driven by time, irrespective of the precise causes, can be confronted with the idea that aging and cancer share common mechanistic grounds that are referred to as 'hallmarks'. Indeed, several hallmarks of aging also contribute to carcinogenesis and tumor progression, but some of the molecular and cellular characteristics of aging may also reduce the probability of developing lethal cancer, perhaps explaining why very old age (> 90 years) is accompanied by a reduced incidence of neoplastic diseases. We will also discuss the possibility that the aging process itself causes cancer, meaning that the time-dependent degradation of cellular and supracellular functions that accompanies aging produces cancer as a byproduct or 'age-associated disease'. Conversely, cancer and its treatment may erode health and drive the aging process, as this has dramatically been documented for cancer survivors diagnosed during childhood, adolescence, and young adulthood. We conclude that aging and cancer are connected by common superior causes including endogenous and lifestyle factors, as well as by a bidirectional crosstalk, that together render old age not only a risk factor of cancer but also an important parameter that must be considered for therapeutic decisions.
Topics: Humans; Aging; Neoplasms; Animals; Disease Susceptibility; Risk Factors
PubMed: 38760832
DOI: 10.1186/s12943-024-02020-z -
PloS One 2024White matter (WM) changes occur throughout the lifespan at a different rate for each developmental period. We aggregated 10879 structural MRIs and 6186...
White matter (WM) changes occur throughout the lifespan at a different rate for each developmental period. We aggregated 10879 structural MRIs and 6186 diffusion-weighted MRIs from participants between 2 weeks to 100 years of age. Age-related changes in gray matter and WM partial volumes and microstructural WM properties, both brain-wide and on 29 reconstructed tracts, were investigated as a function of biological sex and hemisphere, when appropriate. We investigated the curve fit that would best explain age-related differences by fitting linear, cubic, quadratic, and exponential models to macro and microstructural WM properties. Following the first steep increase in WM volume during infancy and childhood, the rate of development slows down in adulthood and decreases with aging. Similarly, microstructural properties of WM, particularly fractional anisotropy (FA) and mean diffusivity (MD), follow independent rates of change across the lifespan. The overall increase in FA and decrease in MD are modulated by demographic factors, such as the participant's age, and show different hemispheric asymmetries in some association tracts reconstructed via probabilistic tractography. All changes in WM macro and microstructure seem to follow nonlinear trajectories, which also differ based on the considered metric. Exponential changes occurred for the WM volume and FA and MD values in the first five years of life. Collectively, these results provide novel insight into how changes in different metrics of WM occur when a lifespan approach is considered.
Topics: Humans; White Matter; Adult; Male; Female; Adolescent; Middle Aged; Aged; Young Adult; Child; Aged, 80 and over; Infant; Child, Preschool; Aging; Longevity; Infant, Newborn; Diffusion Tensor Imaging; Diffusion Magnetic Resonance Imaging; Anisotropy; Brain; Gray Matter
PubMed: 38758830
DOI: 10.1371/journal.pone.0301520 -
Science Advances May 2024A ketogenic diet (KD) is a high-fat, low-carbohydrate diet that leads to the generation of ketones. While KDs improve certain health conditions and are popular for...
A ketogenic diet (KD) is a high-fat, low-carbohydrate diet that leads to the generation of ketones. While KDs improve certain health conditions and are popular for weight loss, detrimental effects have also been reported. Here, we show mice on two different KDs and, at different ages, induce cellular senescence in multiple organs, including the heart and kidney. This effect is mediated through adenosine monophosphate-activated protein kinase (AMPK) and inactivation of mouse double minute 2 (MDM2) by caspase-2, leading to p53 accumulation and p21 induction. This was established using p53 and caspase-2 knockout mice and inhibitors to AMPK, p21, and caspase-2. In addition, senescence-associated secretory phenotype biomarkers were elevated in serum from mice on a KD and in plasma samples from patients on a KD clinical trial. Cellular senescence was eliminated by a senolytic and prevented by an intermittent KD. These results have important clinical implications, suggesting that the effects of a KD are contextual and likely require individual optimization.
Topics: Diet, Ketogenic; Animals; Cellular Senescence; Tumor Suppressor Protein p53; Mice; Humans; Mice, Knockout; Cyclin-Dependent Kinase Inhibitor p21; AMP-Activated Protein Kinases; Proto-Oncogene Proteins c-mdm2; Male; Organ Specificity
PubMed: 38758782
DOI: 10.1126/sciadv.ado1463 -
Science Advances May 2024Acetyl-CoA synthetase short-chain family member 1 (ACSS1) uses acetate to generate mitochondrial acetyl-CoA and is regulated by deacetylation by sirtuin 3. We generated...
Acetyl-CoA synthetase short-chain family member 1 (ACSS1) uses acetate to generate mitochondrial acetyl-CoA and is regulated by deacetylation by sirtuin 3. We generated an ACSS1-acetylation (Ac) mimic mouse, where lysine-635 was mutated to glutamine (K635Q). Male mice were smaller with higher metabolic rate and blood acetate and decreased liver/serum ATP and lactate levels. After a 48-hour fast, mice presented hypothermia and liver aberrations, including enlargement, discoloration, lipid droplet accumulation, and microsteatosis, consistent with nonalcoholic fatty liver disease (NAFLD). RNA sequencing analysis suggested dysregulation of fatty acid metabolism, cellular senescence, and hepatic steatosis networks, consistent with NAFLD. Fasted mouse livers showed increased fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), both associated with NAFLD, and increased carbohydrate response element-binding protein binding to and enhancer regions. Last, liver lipidomics showed elevated ceramide, lysophosphatidylethanolamine, and lysophosphatidylcholine, all associated with NAFLD. Thus, we propose that ACSS1-K635-Ac dysregulation leads to aberrant lipid metabolism, cellular senescence, and NAFLD.
Topics: Animals; Non-alcoholic Fatty Liver Disease; Mice; Cellular Senescence; Acetylation; Mitochondria; Stearoyl-CoA Desaturase; Male; Acetate-CoA Ligase; Gene Knock-In Techniques; Liver; Lipid Metabolism; Sirtuin 3; Disease Models, Animal; Coenzyme A Ligases; Fatty Acid Synthase, Type I
PubMed: 38758779
DOI: 10.1126/sciadv.adj5942 -
Aging Cell May 2024A commentary of the paper 'Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology' that appeared recently in Aging...
A commentary of the paper 'Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology' that appeared recently in Aging Cell. The possible association of a mitochondrial haplogroup with a disease is frequently discussed. The Humanin peptide encoded by the mtDNA has been shown to play an important regulatory role in cell metabolism. There are variants of Humanin caused by different mutations and it is known that the potent form of Humanin, termed S14G, is found naturally in the people of haplogroup U6a7a1a because they have the mutation m.A2672G; however it has not been shown that having this mutation is indeed beneficial. In their paper, the authors suggest that the mitochondrial DNA mutation, m.C2639T, may be beneficial in people who are in haplogroup N1b and also carry APOE4. The mutation changes the common form of Humanin to Humanin P3S. In the study, the researchers looked at a group of Ashkenazi women who were over the age of 95, and found that a higher proportion of them carried APOE4, suggesting that Humanin P3S protected them against the adverse effects of APOE4. A study in a mouse model supported this finding by showing treatment with Humanin P3S reduced APOE4-induced brain pathology. In the world population, there are about 500,000 Ashkenazi in haplogroup N1b, predominantly in the subgroup N1b1b1; and there are about 9.5 million non-Ashkenazi people with the mutation m.C2639T and are therefore also in haplogroup N1b and have Humanin P3S. However, the researchers have yet to show Humanin P3S is of benefit in non-Ashkenazi people. This paper raises the possibility of a therapeutic use of Humanin P3S in the treatment of Alzheimer's disease.
PubMed: 38757793
DOI: 10.1111/acel.14207 -
Frontiers in Aging 2024Various so-called dietary restriction paradigms have shown promise for extending health and life. All such paradigms rely on (hereafter ) feeding, something virtually... (Review)
Review
Various so-called dietary restriction paradigms have shown promise for extending health and life. All such paradigms rely on (hereafter ) feeding, something virtually never employed in animals whose long-term health we value, either as a control or, except for food restriction itself, for both control and treatment arms of the experiment. Even though the mechanism(s) remain only vaguely understood, compared to -fed animals a host of dietary manipulations, including calorie restriction, low protein, methionine, branched-chain amino acids, and even low isoleucine have demonstrable health benefits in laboratory species in a standard laboratory environment. The remaining challenge is to determine whether these health benefits remain in more realistic environments and how they interact with other health enhancing treatments such as exercise or emerging geroprotective drugs. Here we review the current state of the field of amino acid restriction on longevity of animal models and evaluate its translational potential.
PubMed: 38757144
DOI: 10.3389/fragi.2024.1393216 -
Malaria Journal May 2024Emerging artemisinin partial resistance and diagnostic resistance are a threat to malaria control in Africa. Plasmodium falciparum kelch13 (k13) propeller-domain...
BACKGROUND
Emerging artemisinin partial resistance and diagnostic resistance are a threat to malaria control in Africa. Plasmodium falciparum kelch13 (k13) propeller-domain mutations that confer artemisinin partial resistance have emerged in Africa. k13-561H was initially described at a frequency of 7.4% from Masaka in 2014-2015, but not present in nearby Rukara. By 2018, 19.6% of isolates in Masaka and 22% of isolates in Rukara contained the mutation. Longitudinal monitoring is essential to inform control efforts. In Rukara, an assessment was conducted to evaluate recent k13-561H prevalence changes, as well as other key mutations. Prevalence of hrp2/3 deletions was also assessed.
METHODS
Samples collected in Rukara in 2021 were genotyped for key artemisinin and partner drug resistance mutations using molecular inversion probe assays and for hrp2/3 deletions using qPCR.
RESULTS
Clinically validated k13 artemisinin partial resistance mutations continue to increase in prevalence with the overall level of mutant infections reaching 32% in Rwanda. The increase appears to be due to the rapid emergence of k13-675V (6.4%, 6/94 infections), previously not observed, rather than continued expansion of 561H (23.5% 20/85). Mutations to partner drugs and other anti-malarials were variable, with high levels of multidrug resistance 1 (mdr1) N86 (95.5%) associated with lumefantrine decreased susceptibility and dihydrofolate reductase (dhfr) 164L (24.7%) associated with a high level of antifolate resistance, but low levels of amodiaquine resistance polymorphisms with chloroquine resistance transporter (crt) 76T: at 6.1% prevalence. No hrp2 or hrp3 gene deletions associated with diagnostic resistance were found.
CONCLUSIONS
Increasing prevalence of artemisinin partial resistance due to k13-561H and the rapid expansion of k13-675V is concerning for the longevity of artemisinin effectiveness in the region. False negative RDT results do not appear to be an issue with no hrp2 or hpr3 deletions detected. Continued molecular surveillance in this region and surrounding areas is needed to follow artemisinin partial resistance and provide early detection of partner drug resistance, which would likely compromise control and increase malaria morbidity and mortality in East Africa.
Topics: Plasmodium falciparum; Artemisinins; Antimalarials; Protozoan Proteins; Drug Resistance; Rwanda; Malaria, Falciparum; Mutation; Humans; Antigens, Protozoan; Prevalence; Child; Young Adult; Adolescent; Adult; Child, Preschool
PubMed: 38755607
DOI: 10.1186/s12936-024-04981-4 -
Nature Communications May 2024The goal of this study is to examine the association between in utero drought exposure and epigenetic age acceleration (EAA) in a global climate change hot spot....
The goal of this study is to examine the association between in utero drought exposure and epigenetic age acceleration (EAA) in a global climate change hot spot. Calculations of EAA in adults using DNA methylation have been found to accurately predict chronic disease and longevity. However, fewer studies have examined EAA in children, and drought exposure in utero has not been investigated. Additionally, studies of EAA in low-income countries with diverse populations are rare. We assess EAA using epigenetic clocks and two DNAm-based pace-of-aging measurements from whole saliva samples in 104 drought-exposed children and 109 same-sex sibling controls in northern Kenya. We find a positive association between in utero drought exposure and EAA in two epigenetic clocks (Hannum's and GrimAge) and a negative association in the DNAm based telomere length (DNAmTL) clock. The combined impact of drought's multiple deleterious stressors may reduce overall life expectancy through accelerated epigenetic aging.
Topics: Humans; Droughts; Female; Epigenesis, Genetic; Climate Change; Kenya; Male; Child; DNA Methylation; Prenatal Exposure Delayed Effects; Pregnancy; Aging; Saliva; Child, Preschool
PubMed: 38755138
DOI: 10.1038/s41467-024-48426-7