Search

Little is known about the possibility of reversing age-related biological changes when they have already occurred. To explore this, we have characterized the effects of reducing insulin/IGF-1 signaling (IIS) during old age. Reduction of IIS throughout life slows age-related decline in diverse species, most strikingly in the nematode Caenorhabditis elegans. Here we show that even at advanced ages, auxin-induced degradation of DAF-2 in single tissues, including neurons and the intestine, is still able to markedly increase C. eleganslifespan. We describe how reversibility varies among senescent changes. While senescent pathologies that develop in mid-life were not reversed, there was a rejuvenation of the proteostasis network, manifesting as a restoration of the capacity to eliminate otherwise intractable protein aggregates that accumulate with age. Moreover, resistance to several stressors was restored. These results support several new conclusions. (1) Loss of resilience is not solely a consequence of pathologies that develop in earlier life. (2) Restoration of proteostasis and resilience by inhibiting IIS is a plausible cause of the increase in lifespan. And (3), most interestingly, some aspects of the age-related transition from resilience to frailty can be reversed to a certain extent. This raises the possibility that the effect of IIS and related pathways on resilience and frailty during aging in higher animals might possess some degree of reversibility.

How paternal exposure to ionizing radiation affects genetic inheritance and disease risk in the offspring has been a long-standing question in radiation biology. In humans, nearly 80% of transmitted mutations arise in the paternal germline1, but the transgenerational effects of ionizing radiation exposure has remained controversial and the mechanisms are unknown. Here we show that in sex-separated Caenorhabditis elegansstrains, paternal, but not maternal, exposure to ionizing radiation leads to transgenerational embryonic lethality. The offspring of irradiated males displayed various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement and aneuploidy. Paternal DNA double strand breaks were repaired by maternally provided error-prone polymerase theta-mediated end joining. Mechanistically, we show that depletion of an orthologue of human histone H1.0, HIS-24, or the heterochromatin protein HPL-1, could significantly reverse the transgenerational embryonic lethality. Removal of HIS-24 or HPL-1 reduced histone 3 lysine 9 dimethylation and enabled error-free homologous recombination repair in the germline of the F1generation from ionizing radiation-treated P0males, consequently improving the viability of the F2generation. This work establishes the mechanistic underpinnings of the heritable consequences of paternal radiation exposure on the health of offspring, which may lead to congenital disorders and cancer in humans.

The DNA-repair capacity in somatic cells is limited compared with that in germ cells. It has remained unknown whether not only lesion-type-specific, but overall repair capacities could be improved. Here we show that the DREAM repressor complex curbs the DNA-repair capacities in somatic tissues of Caenorhabditis elegans. Mutations in the DREAM complex induce germline-like expression patterns of multiple mechanisms of DNA repair in the soma. Consequently, DREAM mutants confer resistance to a wide range of DNA-damage types during development and aging. Similarly, inhibition of the DREAM complex in human cells boosts DNA-repair gene expression and resistance to distinct DNA-damage types. DREAM inhibition leads to decreased DNA damage and prevents photoreceptor loss in progeroid Ercc1−/−mice. We show that the DREAM complex transcriptionally represses essentially all DNA-repair systems and thus operates as a highly conserved master regulator of the somatic limitation of DNA-repair capacities.

Ageing is a complex, multifaceted process leading to widespread functional decline that affects every organ and tissue, but it remains unknown whether ageing has a unifying causal mechanism or is grounded in multiple sources. Phenotypically, the ageing process is associated with a wide variety of features at the molecular, cellular and physiological level—for example, genomic and epigenomic alterations, loss of proteostasis, declining overall cellular and subcellular function and deregulation of signalling systems. However, the relative importance, mechanistic interrelationships and hierarchical order of these features of ageing have not been clarified. Here we synthesize accumulating evidence that DNA damage affects most, if not all, aspects of the ageing phenotype, making it a potentially unifying cause of ageing. Targeting DNA damage and its mechanistic links with the ageing phenotype will provide a logical rationale for developing unified interventions to counteract age-related dysfunction and disease.

Aging can be defined as a state of progressive functional decline accompanied by an increase in mortality. Time-dependent accumulation of cellular damage, namely lesions and mutations in the DNA and misfolded proteins, impair organellar and cellular function. Ensuing cell fate alterations lead to the accumulation of dysfunctional cells and hamper homeostatic processes, thus limiting regenerative potential; trigger low-grade inflammation; and alter intercellular and intertissue communication. The accumulation of molecular damage together with modifications in the epigenetic landscape, dysregulation of gene expression, and altered endocrine communication, drive the aging process and establish age as the main risk factor for age-associated diseases and multimorbidity.

DNA damage causes cancer, impairs development and accelerates aging. Transcription-blocking lesions and transcription-coupled repair defects lead to developmental failure and premature aging in humans. Following DNA repair, homeostatic processes need to be reestablished to ensure development and maintain tissue functionality. Here, we report that, in Caenorhabditis elegans, removal of the WRAD complex of the MLL/COMPASS H3K4 methyltransferase exacerbates developmental growth retardation and accelerates aging, while depletion of the H3K4 demethylases SPR-5 and AMX-1 promotes developmental growth and extends lifespan amid ultraviolet-induced damage. We demonstrate that DNA-damage-induced H3K4me2 is associated with the activation of genes regulating RNA transport, splicing, ribosome biogenesis and protein homeostasis and regulates the recovery of protein biosynthesis that ensures survival following genotoxic stress. Our study uncovers a role for H3K4me2 in coordinating the recovery of protein biosynthesis and homeostasis required for developmental growth and longevity after DNA damage.

Cardiovascular disease, rare in premenopausal women, increases sharply at menopause and is typically accompanied by chronic inflammation. Previous work in our laboratory demonstrated that replacing senescent ovaries in post-reproductive mice with young, actively cycling ovaries restored many health benefits, including decreased cardiomyopathy and restoration of immune function. Our objective here was to determine if depletion of germ cells from young transplanted ovaries would alter the ovarian-dependent extension of life and health span. Sixty-day-old germ cell-depleted and germ cell-containing ovaries were transplanted to post-reproductive, 17-month-old mice. Mean life span for female CBA/J mice is approximately 644 days. Mice that received germ cell-containing ovaries lived 798 days (maximum = 815 days). Mice that received germ cell-depleted ovaries lived 880 days (maximum = 1046 days), 29% further past the time of surgery than mice that received germ cell-containing ovaries. The severity of inflammation was reduced in all mice that received young ovaries, whether germ cell-containing or germ cell-depleted. Aging-associated inflammatory cytokine changes were reversed in post-reproductive mice by 4 months of new-ovary exposure. In summary, germ cell depletion enhanced the longevity-extending effects of the young, transplanted ovaries and, as with germ cell-containing ovaries, decreased the severity of inflammation, but did so independent of germ cells. Based on these observations, we propose that gonadal somatic cells are programed to preserve the somatic health of the organism with the intent of facilitating future germline transmission. As reproductive potential decreases or is lost, the incentive to preserve the somatic health of the organism is lost as well.

Neurodegenerative disorders, such as Alzheimer’s disease (AD) or Huntington’s disease (HD), are linked to protein aggregate neurotoxicity. According to the “cholinergic hypothesis,” loss of acetylcholine (ACh) signaling contributes to the AD pathology, and therapeutic restoration of ACh signaling is a common treatment strategy. How disease causation and the effect of ACh are linked to protein aggregation and neurotoxicity remains incompletely understood, thus limiting the development of more effective therapies. Here, we show that BAZ-2, the Caenorhabditis elegansortholog of human BAZ2B, limits ACh signaling. baz-2mutations reverse aggregation and toxicity of amyloid-beta as well as polyglutamine peptides, thereby restoring health and lifespan in nematode models of AD and HD, respectively. The neuroprotective effect of Δbaz-2is mediated by choline acetyltransferase, phenocopied by ACh-esterase depletion, and dependent on ACh receptors. baz-2reduction or ectopic ACh treatment augments proteostasis via induction of the endoplasmic reticulum unfolded protein response and the ubiquitin proteasome system.

The genome is constantly attacked by genotoxic insults. DNA damage has long been established as a cause of cancer development through its mutagenic consequences. Conversely, radiation therapy and chemotherapy induce DNA damage to drive cells into apoptosis or senescence as outcomes of the DNA damage response (DDR). More recently, DNA damage has been recognized as a causal factor for the aging process. The role of DNA damage in aging and age-related diseases is illustrated by numerous congenital progeroid syndromes that are caused by mutations in genome maintenance pathways. During the past 2 decades, understanding how DDR drives cancer development and contributes to the aging process has progressed rapidly. It turns out that the DDR factor p53 takes center stage during tumor development and also plays an important role in the aging process. Studies in metazoan models ranging from Caenorhabditis elegans to mammals have revealed cell-autonomous and systemic DDR mechanisms that orchestrate adaptive responses that augment maintenance of the aging organism amid gradually accumulating DNA damage.

DNA damage causally contributes to aging and age-related diseases. Mutations in nucleotide excision repair (NER) genes cause highly complex congenital syndromes characterized by growth retardation, cancer susceptibility, and accelerated aging in humans. Orthologous mutations in Caenorhabditis eleganslead to growth delay, genome instability, and accelerated functional decline, thus allowing investigation of the consequences of persistent DNA damage during development and aging in a simple metazoan model. Here, we conducted proteome, lipidome, and phosphoproteome analysis of NER-deficient animals in response to UV treatment to gain comprehensive insights into the full range of physiological adaptations to unrepaired DNA damage. We derive metabolic changes indicative of a tissue maintenance program and implicate an autophagy-mediated proteostatic response. We assign central roles for the insulin-, EGF-, and AMPK-like signaling pathways in orchestrating the adaptive response to DNA damage. Our results provide insights into the DNA damage responses in the organismal context.

The E4 ligase UFD-2 is required for apoptosis induced by DNA damage in C. elegans, and for the resolution of RAD-51 foci during homologous recombination-dependent repair, thus coordinating these two cellular processes.

Comment on: Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity. Garinis GA, Uittenboogaard LM, Stachelscheid H, Fousteri M, van Ijcken W, Breit TM, van Steeg H, Mullenders LH, van der Horst GT, Brüning JC, Niessen CM, Hoeijmakers JH, Schumacher B. Nat Cell Biol 2009; 11:604-15.

The tumor suppressor p53 is a central player in apoptosis induction in response to oncogenic stimuli and DNA damage. As activation of p53 has been suggested as a prime strategy for future tumor therapy, inhibition of negative regulators of p53 activity would be a similarly desirable strategy. The small worm Caenorhabditis elegansis a model organism in which many conserved biological pathways, including the core apoptotic machinery, were elucidated. The discovery of a worm p53 homolog cep-1/p53 (which stands for C. elegansp53) that specifically induces apoptosis upon DNA damage through a pathway that is conserved from worm to man opened the way for the use of C. elegansgenetics to uncover regulatory mechanisms – and hence novel therapeutic targets – of p53-mediated apoptosis. The authors have recently reported a novel mechanism of C. eleganscep-1/p53 regulation through germ line defective-1-mediated translational repression. This review discusses the potential of the worm system to screen for apoptosis-inducing cancer drugs and to identify novel p53 regulators whose human counterparts might become potential tumor therapy targets.

C. elegansL1 larvae have two well-defined primordial germ cells embedded in a niche comprising two somatic gonad precursor cells. Thus, C. elegansprovides an ideal model for studying intercellular signaling in response to DNA damage. However, existing staining protocols are focused on worms in later developmental stages and are not optimized for the L1 larvae. Here, we present a revised protocol for assessing the DNA damage response utilizing immunofluorescence staining specifically in C. elegansL1 larva.

Cdkn1a, which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of Cdkn1agene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a Cdkn1aSUPERmouse, which harbors an additional Cdkn1aallele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous Kras-driven lung adenocarcinoma model, we show that Cdkn1aSUPERmice display a cancer protection phenotype that is indistinguishable from that observed in Tp53SUPERanimals. Moreover, we demonstrate that Tp53and Cdkn1acooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our Cdkn1aSUPERallele enabled us to assess the contribution of Cdkn1ato Tp53-mediated tumor suppression.