Symposium: Aging, Geroscience and Longevity Special Issue

Peter Fedichev, PhD
Co-founder & CEO, GERO, Singapore

Germline burden of rare damaging variants negatively affects human healthspan and lifespan
Heritability of human lifespan is 23–33% as evident from twin studies. Genome-wide association studies explored this question by linking particular alleles to lifespan traits. However, genetic variants identified so far can explain only a small fraction of lifespan heritability in humans. Here, we report that the burden of rarest protein-truncating variants (PTVs) in two large cohorts is negatively associated with human healthspan and lifespan, accounting for 0.4 and 1.3 years of their variability, respectively. In addition, longer-living individuals possess both fewer rarest PTVs and less damaging PTVs. We further estimated that somatic accumulation of PTVs accounts for only a small fraction of mortality and morbidity acceleration and hence is unlikely to be causal in aging. We conclude that rare damaging mutations, both inherited and accumulated throughout life, contribute to the aging process, and that burden of ultra-rare variants in combination with common alleles better explain apparent heritability of human lifespan.

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Sara Hägg, PhD, Associate Professor
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden
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Measurements of biological age in a Swedish longitudinal study of aging
Biological age measurements are biomarkers associated with the aging process beyond chronological age. Many such measurements exist, from cellular markers, such as telomere length and the epigenetic clock, to more comprehensive markers covering a whole organ or body capacity, such as physical function and frailty. In our longitudinal cohort – the Swedish Adoption/Twin Study of Aging (SATSA) – we followed individuals between 1984-2014 and performed up to nine in-person testings with cognitive and functional assessments, life-style questionnaires and blood draw. Using these data, we developed nine measurements of biological age: telomere length, four types of the epigenetic clock, physiological age, cognitive function, a functional aging index and frailty, and created longitudinal trajectories to track individual changes across old adulthood. Furthermore, we assessed correlations between the biological age measurements, and associations with mortality, both in univariate and multivariate models.

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Dario Riccardo Valenzano
Max Planck Institute for Biology of Ageing, Germany

Intra-species differences in population size shape life history and genome evolution
The evolutionary forces shaping life history divergence within species are largely unknown. Turquoise killifish display differences in lifespan among wild populations, representing an ideal natural experiment in evolution and diversification of life history. By combining genome sequencing and population genetics, we investigate the evolutionary forces shaping lifespan among wild turquoise killifish populations. We generate an improved reference genome assembly and identify genes under positive and purifying selection, as well as those evolving neutrally. Short-lived populations from the outer margin of the species range have small population size and accumulate deleterious mutations in genes significantly enriched in the WNT signaling pathway, neurodegeneration, cancer and the mTOR pathway. We propose that limited population size due to habitat fragmentation and repeated population bottlenecks, by increasing the genome-wide mutation load, exacerbates the effects of mutation accumulation and cumulatively contribute to the short adult lifespan.

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Jonathan An, DDS, PhD
University of Washington, School of Dentistry, Department of Oral Health Sciences, United States

Application of Geroscience to Extend the Oral Healthspan
With the population aging, older adults are a growing patient demographic in dental practices. While disease-specific, replacement-focus questions have led to significant advancements in helping older adults manage oral diseases or restore function and esthetics, there has been a lack of progress in delaying and even reversing the onset and progression of age-related oral deterioration. Consequently, a majority of treatments in older adults are completed after the disease or dysfunction progresses. Thus, implementing Geroscience Initiatives within oral health research will help translate findings and therapeutics more reliably to prevent or reverse age-associated oral dysfunction and disease in people. In this talk, we will explore the oral cavity using normative aged mice, discuss the impact of Geroscience interventions in the aging oral cavity, and share new developments in our goal to bridge the interface of aging biology and oral biology to extend the oral healthspan in people.

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Mounir El Maï, PhD
Institute for Research on Cancer and Aging of Nice (IRCAN), INSERM, France

Switch from apoptosis to senescence results from conflicting tissue proliferative demands to cells unable to proliferate
Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, proliferative tissues exhibit DNA damage and p53-dependent apoptosis, but no senescence. This dampening of tissue renewal capacity leads to loss of cellularity and tissue damage which activates a compensatory pro-proliferative mTOR/Akt signaling pathway in older animals. Inhibition of FoxO transcription factors by Akt results then in reduced SOD2 expression causing an increase of ROS and mitochondrial dysfunction. These alterations induce p15/16 growth arrest and senescence. Therefore, we propose an age-dependent apoptosis-to-senescence switch that results from the integration of pro-proliferative external cues in response to tissue damage within a context of cell autonomous breaks that inhibit cell proliferation.

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Morgan Levine, PhD, Assistant Professor
Yale School of Medicine, United States

A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin
Robust biomarkers of aging have been developed from DNA methylation in humans and more recently, in mice. This study aimed to generate a novel epigenetic clock in rats—a model with unique physical, physiological, and biochemical advantages—by incorporating behavioral data, unsupervised machine learning, and network analysis to identify epigenetic signals that not only track with age, but also relates to phenotypic aging. Reduced representation bisulfite sequencing (RRBS) data was used to train an epigenetic age (DNAmAge) measure in Fischer 344 CDF (F344) rats. This measure correlated with age at (r = 0.93) in an independent sample, and related to physical functioning (p=5.9e-3), after adjusting for age and cell counts. DNAmAge was also found to correlate with age in male C57BL/6 mice (r = 0.79), and was decreased in response to caloric restriction. Our signatures driven by CpGs in intergenic regions that showed substantial overlap with H3K9me3, H3K27me3, and E2F1 transcriptional factor binding.

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Dudley Lamming, PhD, Associate Professor
University of Wisconsin-Madison, United States

Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging
Inhibition of mTOR (mechanistic Target Of Rapamycin) signaling by rapamycin promotes healthspan and longevity more strongly in females than males, perhaps because inhibition of hepatic mTORC2 (mTOR Complex 2) specifically reduces the lifespan of males. Here, we demonstrate using gonadectomy that the sex-specific impact of reduced hepatic mTORC2 is not reversed by depletion of sex hormones. Intriguingly, we find that ovariectomy uncouples lifespan from metabolic health, with ovariectomized females having improved survival despite paradoxically having increased adiposity and decreased control of blood glucose levels. Further, ovariectomy unexpectedly promotes midlife survival of female mice lacking hepatic mTORC2, significantly increasing the survival of those mice that do not develop cancer. In addition to identifying a sex hormone-dependent role for hepatic mTORC2 in female longevity, our results demonstrate that metabolic health is not inextricably linked to lifespan in mammals, and highlight the importance of evaluating healthspan in mammalian longevity studies.

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Amanda Kowalczyk, PhD Candidate
Carnegie Mellon University – University of Pittsburgh Joint PhD Program in Computational Biology, United States

Pan-mammalian analysis of molecular constraints underlying extended lifespan
Much research to identify the genetic basis of long life has focused on seeking unique genetic changes in exceptionally long-lived species like the naked mole-rat, bats, and the bowhead whale. Unfortunately, such species-specific adaptations do not often generalize to other mammals, including humans. To find pan-mammalian lifespan-regulating genes that may play a role in human longevity, we use a comparative genomics approach to identify convergent genetic changes associated with longevity across all mammals. Our novel computational method identifies associations between evolutionary rates and continuous phenotypes to find a slew of genes that implicate broad-scale functions such as cell cycle control, immune function, and DNA repair in lifespan extension. Considered together, these functions imply that effective cancer control is a key adaptation underlying the evolution of extreme longevity.

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Michael Polymenis, PhD, Professor
Department of Biochemistry and Biophysics, Texas A&M University, United States

​​​​​​Coupling one carbon metabolism with longevity
We queried actively dividing ribosomal protein mutants to answer why some of them have altered cell cycle kinetics and longer replicative lifespan. Our data link transcriptional, translational, and metabolic changes to phenotypes associated with the loss of specific ribosomal proteins. We uncovered translational control of transcripts encoding enzymes of methionine and serine metabolism, which are part of one-carbon (1C) pathways. Cells lacking Rpl22Ap, which are long-lived, have lower levels of metabolites associated with 1C metabolism. Loss of 1C enzymes increased the longevity of wild type cells. 1C pathways exist in all organisms and targeting the relevant enzymes could represent longevity interventions.

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Nicole Jenkins, PhD, Senior Research Officer
Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia

Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging Caenorhabditis elegans
All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis, all depend on iron metabolism. Ferrous iron is known to accumulate over adult lifetime in Caenorhabditis elegans. We found that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrated that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigated age-related cell death and markedly increased lifespan and healthspan. Temporal scaling of lifespan was not evident when ferroptosis was inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant aging rate. Because excess age-related iron elevation in somatic tissue, particularly in brain, is thought to contribute to degenerative disease, post-developmental interventions to limit ferroptosis may promote healthy aging.

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Hosni Cherif, PhD
McGill University, Canada

Senolytics to reduce pain and degeneration in human intervertebral discs
Intervertebral disc (IVDs) degeneration is one of the major causes of back pain. Cellular senescence is a state of stable cell cycle arrest in response to a variety of cellular stresses including oxidative stress and adverse load. The accumulation of senescent IVD cells in the tissue suggest a crucial role in the initiation and development of painful IVD degeneration. Senescent cells secrete an array of cytokines, chemokines, growth factors, and proteases known as the senescence-associated secretory phenotype (SASP). The SASP promote matrix catabolism and inflammation in IVDs thereby accelerating the process of degeneration. This study demonstrates the potential of a natural (o-Vanillin) and a synthetic (RG-7112) senolytic compounds to remove senescent IVD cells, decrease SASP factors release, reduce the inflammatory environment and enhance the IVD matrix production. Removal of senescent cells, using senolytics drugs, could lead to improved therapeutic interventions and ultimately decrease pain and a provide a better quality of life of patients living with intervertebral disc degeneration and low back pain.

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Ying Ann Chiao, PhD, Assistant Member
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, United States

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice
Mitochondrial dysfunction plays a central role in aging and cardiovascular disease. However, it was unclear whether improving mitochondrial function at late-life can rescue pre-existing age-related cardiac dysfunction, especially diastolic dysfunction. Here, we show that 8-week treatment with a mitochondrial-targeted peptide SS-31 (elamipretide) can substantially reverse pre-existing cardiac dysfunction in old mice. At molecular levels, late-life SS-31 treatment reduces mitochondrial ROS levels and normalizes age-related increases in mitochondrial proton leak and protein oxidative modifications. Late-life viral expression of mitochondrial-targeted catalase (mCAT) similarly improves diastolic function in old mice. SS-31 treatment cannot further improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. Our results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and support the therapeutic potentials of mitochondrial-targeted interventions in cardiac aging.

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Fivos Borbolis, PhD, Post-doctoral Researcher
Biomedical Research Foundation of the Academy of Athens, Greece

mRNA decapping as a modulator of ageing and development
Eukaryotic mRNAs are characterized by a methylated guanine cap structure that is added co-transcriptionally at the 5’ end of all molecules generated by RNA polymerase II. This 5’-cap defines key aspects of an mRNA’s lifecycle through its interactions with various cap-binding proteins. Although removal of the 5’-cap (decapping) is the first step in the major 5’-3’ mRNA decay pathway, recent findings revealed that decapped transcripts are not committed to degradation but can also be stored, maintaining the potential to be recapped and return to the translational pool. Such observations elevated decapping from a procedural step in bulk mRNA decay to a sophisticated mechanism that can control gene expression. Our work concerning DCAP-1/DCP1, the essential co-factor of the major cytoplasmic mRNA decapping enzyme in two model systems, reveals that the process of decapping is utilized in neuronal cells to modulate neuroendocrine signals that control development and ageing. In Caenorhabditis elegans neuronal DCAP-1 affects the stability of ins-7 mRNA, encoding a neurosecreted insulin-like peptide, which acts in the intestine to regulate the function of insulin/IGF-like signaling and determine lifespan. Overexpression of DCAP-1 exclusively in the worm’s neurons is thereby sufficient to promote longevity, while its deficiency shortens lifespan and impacts developmental decisions. Likewise, DCP1 neuronal overexpression confers longevity in Drosophila melanogaster adults, and its neuronal knockdown shortens lifespan and affects wing morphogenesis, cell non-autonomously. Our analysis suggests a critical and conserved function of DCAP-1/DCP1 in lifespan modulation and the control of developmental events.

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