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Telomere length, gene expression, blood chemical parameters and DNA-methylation status all undergo age-associated changes, which can be measured and used to predict chronological age ...with a varying error rate. This review focuses on technical approaches used to construct aging clocks and compares their efficiency.
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•Biohorology is the science of measuring the passage of time in living systems.•Today there are dozens of aging clocks based on such biomarkers of aging as DNAm, gene expression and metabolomic profiles.•DNAm clocks are the most popular so far, but they have a number of frequently overlooked technical drawbacks.•Deep learning methods can be used to develop aging clocks using data types previously deemed too complicated.•Deep learning methods can also be used to extend aging clocks’ functionality beyond age prediction.
The aging process results in multiple traceable footprints, which can be quantified and used to estimate an organism's age. Examples of such aging biomarkers include epigenetic changes, telomere attrition, and alterations in gene expression and metabolite concentrations. More than a dozen aging clocks use molecular features to predict an organism's age, each of them utilizing different data types and training procedures. Here, we offer a detailed comparison of existing mouse and human aging clocks, discuss their technological limitations and the underlying machine learning algorithms. We also discuss promising future directions of research in biohorology — the science of measuring the passage of time in living systems. Overall, we expect deep learning, deep neural networks and generative approaches to be the next power tools in this timely and actively developing field.
Selenium is an essential trace element in mammals due to its presence in proteins in the form of selenocysteine (Sec). Human genome codes for 25 Sec-containing protein genes, and mouse and rat ...genomes for 24.
We characterized the selenoproteomes of 44 sequenced vertebrates by applying gene prediction and phylogenetic reconstruction methods, supplemented with the analyses of gene structures, alternative splicing isoforms, untranslated regions, SECIS elements, and pseudogenes. In total, we detected 45 selenoprotein subfamilies. 28 of them were found in mammals, and 41 in bony fishes. We define the ancestral vertebrate (28 proteins) and mammalian (25 proteins) selenoproteomes, and describe how they evolved along lineages through gene duplication (20 events), gene loss (10 events) and replacement of Sec with cysteine (12 events). We show that an intronless selenophosphate synthetase 2 gene evolved in early mammals and replaced functionally the original multiexon gene in placental mammals, whereas both genes remain in marsupials. Mammalian thioredoxin reductase 1 and thioredoxin-glutathione reductase evolved from an ancestral glutaredoxin-domain containing enzyme, still present in fish. Selenoprotein V and GPx6 evolved specifically in placental mammals from duplications of SelW and GPx3, respectively, and GPx6 lost Sec several times independently. Bony fishes were characterized by duplications of several selenoprotein families (GPx1, GPx3, GPx4, Dio3, MsrB1, SelJ, SelO, SelT, SelU1, and SelW2). Finally, we report identification of new isoforms for several selenoproteins and describe unusually conserved selenoprotein pseudogenes.
This analysis represents the first comprehensive survey of the vertebrate and mammal selenoproteomes, and depicts their evolution along lineages. It also provides a wealth of information on these selenoproteins and their forms.
Metabolism, homeostasis, and aging Moldakozhayev, Alibek; Gladyshev, Vadim N.
Trends in endocrinology and metabolism,
03/2023, Letnik:
34, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Metabolism can be categorized by resource abundance or depletion.Resource abundance drives the pursuit type of metabolism and consists of anabolism and catabolism.Resource depletion, accompanied by ...metabolic waste accumulation as a result of pursuit, activates the maintenance type of metabolism and consists of damage pre-emption and clearance mechanisms.The organismal sensory system mediates pendulum-like swings between pursuit and maintenance states in an attempt to sustain the least deleterious state: homeostasis.Swings represent imperfect metabolic reactions and generate deleterious metabolic consequences.Adjusting environmental signals close to neutral may lower the magnitude of metabolic swings, extend the periods near the homeostatic point, and extend lifespan.Analyzing pathways activated by metabolic waste could help to identify new interventions to slow aging.
We propose a two-mode (pursuit/maintenance) model of metabolism defined by usable resource availability. Pursuit, consisting of anabolism and catabolism, dominates when usable resources are plentiful and leads to the generation of metabolic waste. In turn, maintenance of a system is activated by elevated metabolic waste during resource depletion. Interaction with the environment results in pendulum-like swings between these metabolic states in thriveless attempts to maintain the least deleterious organismal state – ephemeral homeostasis. Imperfectness of biological processes during these attempts supports the accumulation of the deleteriome, driving organismal aging. We discuss how metabolic adjustment by the environment and resource stabilization may modulate healthspan and lifespan.
Ribosome profiling has emerged as a powerful method to assess global gene translation, but methodological and analytical challenges often lead to inconsistencies across labs and model organisms. A ...critical issue in ribosome profiling is nuclease treatment of ribosome-mRNA complexes, as it is important to ensure both stability of ribosomal particles and complete conversion of polysomes to monosomes. We performed comparative ribosome profiling in yeast and mice with various ribonucleases including I, A, S7 and T1, characterized their cutting preferences, trinucleotide periodicity patterns and coverage similarities across coding sequences, and showed that they yield comparable estimations of gene expression when ribosome integrity is not compromised. However, ribosome coverage patterns of individual transcripts had little in common between the ribonucleases. We further examined their potency at converting polysomes to monosomes across other commonly used model organisms, including bacteria, nematodes and fruit flies. In some cases, ribonuclease treatment completely degraded ribosome populations. Ribonuclease T1 was the only enzyme that preserved ribosomal integrity while thoroughly converting polysomes to monosomes in all examined species. This study provides a guide for ribonuclease selection in ribosome profiling experiments across most common model systems.
Organismal aging is inherently connected to the aging of its constituent cells and systems. Reducing the biological age of the organism may be assisted by reducing the age of its cells - an approach ...exemplified by partial cell reprogramming through the expression of Yamanaka factors or exposure to chemical cocktails. It is crucial to protect cell type identity during partial reprogramming, as cells need to retain or rapidly regain their functions following the treatment. Another critical issue is the ability to quantify biological age as reprogrammed older cells acquire younger states. We discuss recent advances in reprogramming-induced rejuvenation and offer a critical review of this procedure and its relationship to the fundamental nature of aging. We further comparatively analyze partial reprogramming, full reprogramming and transdifferentiation approaches, assess safety concerns and emphasize the importance of distinguishing rejuvenation from dedifferentiation. Finally, we highlight translational opportunities that the reprogramming-induced rejuvenation approach offers.
Dietary restriction (DR) without malnutrition encompasses numerous regimens with overlapping benefits including longevity and stress resistance, but unifying nutritional and molecular mechanisms ...remain elusive. In a mouse model of DR-mediated stress resistance, we found that sulfur amino acid (SAA) restriction increased expression of the transsulfuration pathway (TSP) enzyme cystathionine γ-lyase (CGL), resulting in increased hydrogen sulfide (H2S) production and protection from hepatic ischemia reperfusion injury. SAA supplementation, mTORC1 activation, or chemical/genetic CGL inhibition reduced H2S production and blocked DR-mediated stress resistance. In vitro, the mitochondrial protein SQR was required for H2S-mediated protection during nutrient/oxygen deprivation. Finally, TSP-dependent H2S production was observed in yeast, worm, fruit fly, and rodent models of DR-mediated longevity. Together, these data are consistent with evolutionary conservation of TSP-mediated H2S as a mediator of DR benefits with broad implications for clinical translation.
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•Sulfur amino acid restriction is a key nutritional determinant of dietary restriction•Cysteine restriction enhances endogenous CGL activity and H2S production•Increased H2S is necessary and sufficient for DR-mediated stress resistance•Increased H2S is shared by DR regimens in yeast, worms, flies, and rodents
Dietary restriction (DR) improves stress resistance and extends lifespan in a variety of organisms. One of the ways DR is found to work is by increasing endogenous production the gas hydrogen sulfide (H2S) that acts as a hormetic compound with numerous health benefits.
Summary
Aging is characterized by numerous molecular changes, such as accumulation of molecular damage and altered gene expression, many of which are linked to DNA methylation. Here, we characterize ...the blood DNA methylome across 16 age groups of mice and report numerous global, region‐ and site‐specific features, as well as the associated dynamics of methylation changes. Transition of the methylome throughout lifespan was not uniform, with many sites showing accelerated changes in late life. The associated genes and promoters were enriched for aging‐related pathways, pointing to a fundamental link between DNA methylation and control of the aging process. Calorie restriction both shifted the overall methylation pattern and was accompanied by its gradual age‐related remodeling, the latter contributing to the lifespan‐extending effect. With age, both highly and poorly methylated sites trended toward intermediate levels, and aging was accompanied by an accelerated increase in entropy, consistent with damage accumulation. However, the entropy effects differed for the sites that increased, decreased and did not change methylation with age. Many sites trailed behind, whereas some followed or even exceeded the entropy trajectory and altered the developmental DNA methylation pattern. The patterns we observed in certain genomic regions were conserved between humans and mice, suggesting common principles of functional DNA methylome remodeling and its critical role in aging. The highly resolved DNA methylome remodeling provides an excellent model for understanding systemic changes that characterize the aging process.
Selenium is incorporated into selenoproteins as the 21st amino acid selenocysteine (Sec). There are 25 selenoproteins encoded in the human genome, and their synthesis requires a dedicated machinery. ...Most selenoproteins are oxidoreductases with important functions in human health. A number of disorders have been associated with deficiency of selenoproteins, caused by mutations in selenoprotein genes or Sec machinery genes. We discuss mutations that are known to cause disease in humans and report their allele frequencies in the general population. The occurrence of protein-truncating variants in the same genes is also presented. We provide an overview of pathogenic variants in selenoproteins genes from a population genomics perspective.
Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells and tissues accumulate abundant ...cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS. Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number, and type I interferons were elevated in the wild-type aged mice. As sterile inflammation is a hallmark of aging, we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.
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•SIRT6 KO mice accumulate L1 cDNA, triggering interferon response via cGAS pathway•Wild-type aged mice accumulate L1 cDNA and display type I interferon response•Reverse-transcriptase inhibitors rescue type I interferon response and DNA damage•Reverse-transcriptase inhibitors extend lifespan and improve health of SIRT6 KO mice
Simon et al. show that LINE1 retrotransposon elements are derepressed in aged and progeroid mice. Cytoplasmic accumulation of LINE1 cDNA copies induced a type I interferon response, through the cGAS DNA sensing pathway, resulting in pathological inflammation. Inhibiting L1 replication significantly improved the health and lifespan of aged mice.
Redox control of protein function involves oxidation and reduction of amino acid residues, but the mechanisms and regulators involved are insufficiently understood. Here, we report that in ...conjunction with Mical proteins, methionine-R-sulfoxide reductase B1 (MsrB1) regulates mammalian actin assembly via stereoselective methionine oxidation and reduction in a reversible, site-specific manner. Two methionine residues in actin are specifically converted to methionine-R-sulfoxide by Mical1 and Mical2 and reduced back to methionine by selenoprotein MsrB1, supporting actin disassembly and assembly, respectively. Macrophages utilize this redox control during cellular activation by stimulating MsrB1 expression and activity as a part of innate immunity. We identified the regulatory role of MsrB1 as a Mical antagonist in orchestrating actin dynamics and macrophage function. More generally, our study shows that proteins can be regulated by reversible site-specific methionine-R-sulfoxidation.
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•Mical and MsrB regulate actin through stereospecific methionine oxidation/reduction•Met oxidation depolymerizes actin and reduction promotes actin repolymerization•Selenoprotein MsrB1 regulates actin polymerization in response to LPS stimulation•Proteins can be regulated by reversible site-specific methionine-R-sulfoxidation
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