DNA mutations in somatic cells have been implicated in the causation of aging, with longer-lived species having a higher capacity to maintain genome sequence integrity than shorter-lived species. In ...an attempt to directly test this hypothesis, we used single-cell whole-genome sequencing to analyze spontaneous and bleomycin-induced somatic mutations in lung fibroblasts of four rodent species with distinct maximum life spans, including mouse, guinea pig, blind mole-rat, and naked mole-rat, as well as humans. As predicted, the mutagen-induced mutation frequencies inversely correlated with species-specific maximum life span, with the greatest difference observed between the mouse and all other species. These results suggest that long-lived species are capable of processing DNA damage in a more accurate way than short-lived species.
Accumulation of somatic mutations is thought to contribute to the aging process. Genomic instability has been shown to increase during aging, suggesting an aberrant function of DNA doublestrand break ...(DSB) repair. Surprisingly, DSB repair has not been examined with respect to cellular senescence. Therefore, we have studied the ability of young, presenescent, and senescent normal human fibroblasts to repair DSBs in transfected DNA by using a fluorescent reporter substrate. We have found that the efficiency of end joining is reduced up to 4.5 fold in presenescent and senescent cells, relative to young cells. Sequence analysis of end junctions showed that the frequency of precise ligation was higher in young cells, whereas end joining in old cells was associated with extended deletions. These results indicate that end joining becomes inefficient and more error-prone during cellular senescence. Furthermore, the ability to use microhomologies for end joining was compromised in senescent cells, suggesting that young and senescent cells may use different end joining pathways. We hypothesize that inefficient and aberrant end joining is a likely mechanism underlying the age-related genomic instability and higher incidence of cancer in the elderly.
Sirtuin 6 (SIRT6) has been in the spotlight of aging research because progeroid phenotypes are associated with SIRT6 deficiency. SIRT6 has multiple molecular functions, including DNA repair and ...heterochromatin regulation, which position SIRT6 as a hub that regulates genome and epigenome stability. Genomic instability caused by persistent DNA damage and accumulating mutations, together with alterations in the epigenetic landscape and derepression of repetitive genetic elements, have emerged as mechanisms driving organismal aging. Enhanced levels of SIRT6 expression or activity provide avenues for rejuvenation strategies. This review focuses on the role of SIRT6 in the maintenance of genome and epigenome stability and its link to longevity. We propose a model where SIRT6 together with lamins control aging and rejuvenation by maintaining epigenetic silencing of repetitive elements.
Sirtuin 6 (SIRT6) extends mammalian lifespan and promotes healthspan.SIRT6 maintains genomic stability through improved efficiency of DNA repair.SIRT6 maintains heterochromatin and silences repetitive genetic elements.Regulation of SIRT6 is a potential strategy for rejuvenation.
Genomic instability is an important driver of ageing. The accumulation of DNA damage is believed to contribute to ageing by inducing cell death, senescence and tissue dysfunction. However, emerging ...evidence shows that inflammation is another major consequence of DNA damage. Inflammation is a hallmark of ageing and the driver of multiple age-related diseases. Here, we review the evidence linking DNA damage, inflammation and ageing, highlighting how premature ageing syndromes are associated with inflammation. We discuss the mechanisms by which DNA damage induces inflammation, such as through activation of the cGAS-STING axis and NF-κB activation by ATM. The triggers for activation of these signalling cascades are the age-related accumulation of DNA damage, activation of transposons, cellular senescence and the accumulation of persistent R-loops. We also discuss how epigenetic changes triggered by DNA damage can lead to inflammation and ageing via redistribution of heterochromatin factors. Finally, we discuss potential interventions against age-related inflammation.
Cells subjected to sub-lethal doses of stress such as irradiation or oxidative damage enter a state that closely resembles replicative senescence. What triggers stress-induced premature senescence ...(SIPS) and how similar this mechanism is to replicative senescence are not well understood. It has been suggested that stress-induced senescence is caused by rapid telomere shortening resulting from DNA damage. In order to test this hypothesis directly, we examined whether overexpression of the catalytic subunit of human telomerase (hTERT) can protect cells from SIPS. We therefore analyzed the response of four different lines of normal human fibroblasts with and without hTERT to stress induced by UV, γ-irradiation, and H2O2. SIPS was induced with the same efficiency in normal and hTERT-immortalized cells. This suggests that SIPS is not triggered by telomere shortening and that nonspecific DNA damage serves as a signal for induction of SIPS. Although telomerase did not protect cells from SIPS, fibroblasts expressing hTERT were more resistant to stress-induced apoptosis and necrosis. We hypothesize that healing of DNA breaks by telomerase inhibits the induction of cell death, but because healing does not provide legitimate DNA repair, it does not protect cells from SIPS.
For centuries, people believed that bats possessed sinister powers. Bats are thought to be ancestral hosts to many deadly viruses affecting humans including Ebola, rabies, and most recently ...SARS-CoV-2 coronavirus. However, bats themselves tolerate these viruses without ill effects. The second power that bats have is their longevity. Bats live much longer than similar-sized land mammals. Here we review how bats’ ability to control inflammation may be contributing to their longevity. The underlying mechanisms may hold clues to developing new treatments for age-related diseases. Now may be the time to use science to exploit the secret powers of bats for human benefit.
Bats host and tolerate a wide range of viruses and live considerably longer than similar-sized land mammals. Here, Gorbunova et al. review mechanisms shaping the exceptional longevity and virus resistance of bats. The authors discuss how the bat’s ability to downregulate inflammation may ameliorate age-related diseases, and they propose anti-aging interventions for humans based upon the evolutionary adaptations of bats.
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Unlike aged somatic cells, which exhibit a decline in molecular fidelity and eventually reach a state of replicative senescence, pluripotent stem cells can indefinitely replenish themselves while ...retaining full homeostatic capacity. The conferment of beneficial-pluripotency related traits via
partial cellular reprogramming in vivo partial reprogramming significantly extends lifespan and restores aging phenotypes in mouse models. Although the phases of cellular reprogramming are well characterized, details of the rejuvenation processes are poorly defined. To understand whether cellular reprogramming can ameliorate DNA damage, we created a reprogrammable accelerated aging mouse model with an ERCC1 mutation. Importantly, using enhanced partial reprogramming by combining small molecules with the Yamanaka factors, we observed potent reversion of DNA damage, significant upregulation of multiple DNA damage repair processes, and restoration of the epigenetic clock. In addition, we present evidence that pharmacological inhibition of ALK5 and ALK2 receptors in the TGFb pathway are able to phenocopy some benefits including epigenetic clock restoration suggesting a role in the mechanism of rejuvenation by partial reprogramming.
Aging is a major risk factor for multiple diseases. Understanding the underlying mechanisms of aging would help to delay and prevent age-associated diseases. Short-lived model organisms have been ...extensively used to study the mechanisms of aging. However, these short-lived species may be missing the longevity mechanisms that are needed to extend the lifespan of an already long-lived species such as humans. Unconventional long-lived animal species are an excellent resource to uncover novel mechanisms of longevity and disease resistance. Here, we review mechanisms that evolved in nonmodel vertebrate species to counteract age-associated diseases. Some antiaging mechanisms are conserved across species; however, various nonmodel species also evolved unique mechanisms to delay aging and prevent disease. This variety of antiaging mechanisms has evolved due to the remarkably diverse habitats and behaviors of these species. We propose that exploring a wider range of unconventional vertebrates will provide important resources to study antiaging mechanisms that are potentially applicable to humans.
Bat crazy iPSCs Athar, Fathima; Seluanov, Andrei; Gorbunova, Vera
Cell,
03/2023, Letnik:
186, Številka:
5
Journal Article
Recenzirano
Accelerating the development of tools for non-model animal research, Dejosez et al. report the generation of induced pluripotent stem cells (iPSCs) from bats using a modified Yamanaka protocol. Their ...study also reveals that bat genomes harbor diverse and unusually abundant endogenous retroviruses (ERVs) that are reactivated during iPSC reprogramming.
Accelerating the development of tools for non-model animal research, Dejosez et al. report the generation of induced pluripotent stem cells (iPSCs) from bats using a modified Yamanaka protocol. Their study also reveals that bat genomes harbor diverse and unusually abundant endogenous retroviruses (ERVs) that are reactivated during iPSC reprogramming.
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