Aging and drug discovery

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Abstract

Multiple interventions in the aging process have been discovered to extend the healthspan of model organisms. Both industry and academia are therefore exploring possible transformative molecules that target aging and age-associated diseases. In this overview, we summarize the presented talks and discussion points of the 5th Annual Aging and Drug Discovery Forum 2018 in Basel, Switzerland. Here academia and industry came together, to discuss the latest progress and issues in aging research. The meeting covered talks about the mechanistic cause of aging, how longevity signatures may be highly conserved, emerging biomarkers of aging, possible interventions in the aging process and the use of artificial intelligence for aging research and drug discovery. Importantly, a consensus is emerging both in industry and academia, that molecules able to intervene in the aging process may contain the potential to transform both societies and healthcare.

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Most cited references 42

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Antioxidants prevent health-promoting effects of physical exercise in humans.

Michael Ristow, Kim Zarse, Andreas Oberbach … (2009)

Exercise promotes longevity and ameliorates type 2 diabetes mellitus and insulin resistance. However, exercise also increases mitochondrial formation of presumably harmful reactive oxygen species (ROS). Antioxidants are widely used as supplements but whether they affect the health-promoting effects of exercise is unknown. We evaluated the effects of a combination of vitamin C (1000 mg/day) and vitamin E (400 IU/day) on insulin sensitivity as measured by glucose infusion rates (GIR) during a hyperinsulinemic, euglycemic clamp in previously untrained (n = 19) and pretrained (n = 20) healthy young men. Before and after a 4 week intervention of physical exercise, GIR was determined, and muscle biopsies for gene expression analyses as well as plasma samples were obtained to compare changes over baseline and potential influences of vitamins on exercise effects. Exercise increased parameters of insulin sensitivity (GIR and plasma adiponectin) only in the absence of antioxidants in both previously untrained (P < 0.001) and pretrained (P < 0.001) individuals. This was paralleled by increased expression of ROS-sensitive transcriptional regulators of insulin sensitivity and ROS defense capacity, peroxisome-proliferator-activated receptor gamma (PPARgamma), and PPARgamma coactivators PGC1alpha and PGC1beta only in the absence of antioxidants (P < 0.001 for all). Molecular mediators of endogenous ROS defense (superoxide dismutases 1 and 2; glutathione peroxidase) were also induced by exercise, and this effect too was blocked by antioxidant supplementation. Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.

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Cellular Senescence: A Translational Perspective

James Kirkland, Tamara Tchkonia (2017)

Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions. We used a hypothesis-driven approach to discover pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) and, based on these SCAPs, the first senolytic agents, drugs that cause senescent cells to become susceptible to their own pro-apoptotic microenvironment. Several senolytic agents, which appear to alleviate multiple senescence-related phenotypes in pre-clinical models, are beginning the process of being translated into clinical interventions that could be transformative.

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Aging of blood can be tracked by DNA methylation changes at just three CpG sites

Carola Weidner, Qiong Lin, Carmen Koch … (2014)

Background Human aging is associated with DNA methylation changes at specific sites in the genome. These epigenetic modifications may be used to track donor age for forensic analysis or to estimate biological age. Results We perform a comprehensive analysis of methylation profiles to narrow down 102 age-related CpG sites in blood. We demonstrate that most of these age-associated methylation changes are reversed in induced pluripotent stem cells (iPSCs). Methylation levels at three age-related CpGs - located in the genes ITGA2B, ASPA and PDE4C - were subsequently analyzed by bisulfite pyrosequencing of 151 blood samples. This epigenetic aging signature facilitates age predictions with a mean absolute deviation from chronological age of less than 5 years. This precision is higher than age predictions based on telomere length. Variation of age predictions correlates moderately with clinical and lifestyle parameters supporting the notion that age-associated methylation changes are associated more with biological age than with chronological age. Furthermore, patients with acquired aplastic anemia or dyskeratosis congenita - two diseases associated with progressive bone marrow failure and severe telomere attrition - are predicted to be prematurely aged. Conclusions Our epigenetic aging signature provides a simple biomarker to estimate the state of aging in blood. Age-associated DNA methylation changes are counteracted in iPSCs. On the other hand, over-estimation of chronological age in bone marrow failure syndromes is indicative for exhaustion of the hematopoietic cell pool. Thus, epigenetic changes upon aging seem to reflect biological aging of blood.

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Author and article information

Journal

Journal ID (nlm-ta): Aging (Albany NY)

Journal ID (iso-abbrev): Aging (Albany NY)

Journal ID (publisher-id): Aging

Title: Aging (Albany NY)

Publisher: Impact Journals

ISSN (Electronic): 1945-4589

Publication date Collection: November 2018

Publication date (Electronic): 13 November 2018

Volume: 10

Issue: 11

Pages: 3079-3088

Affiliations

[1 ]Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen , Copenhagen, , Denmark

[2 ]Pharmaceutical Artificial Intelligence Department, Insilico Medicine, Inc. , Baltimore, , MD, 20850, USA

[3 ]Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania , Philadelphia, , PA, 19104, USA

[4 ]Department of Physiology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, , PA, 19104, USA

[5 ]Buck Institute for Research on Aging , Novato, , CA, 94945, USA

[6 ]Lawrence Berkeley National Laboratory, Life Sciences Division , Berkeley, , CA, 94720, USA

[7 ]Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute for Technology (ETH) Zürich , Switzerland

[8 ]Youth Laboratories , Moscow, , Russia

[9 ]Division of Genetics, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital , Boston, , MA, 02115, USA

[10 ]Belozersky Institute of Physico-Chemical Biology, Moscow State University , Moscow, , Russia

[11 ]Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada

[12 ]Pathway Rx Ltd, Lethbridge, Alberta, Canada

[13 ]Department of Medicine, University of Wisconsin-Madison , Madison, , WI, 53706, USA

[14 ]Department of Human Genetics, Leiden University Medical Center , Leiden, , The Netherlands

[15 ]Pancreatic Islet Development and Regeneration Unit/Laboratory of Aging Biology, Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide , Seville, , Spain

[16 ]Department of Biomedical Sciences, University of Antwerp , Antwerp, , Belgium

[17 ]Translational Neurobiology Group, Center of Molecular Neurology, VIB, Antwerp, , Belgium

[18 ]Engelhardt Institute of Molecular Biology, Russian Academy of Sciences , Moscow, , Russia

[19 ]Institute of Biology of Komi Science Center of Ural Branch of RAS , Syktyvkar, , Russia

[20 ]Moscow Institute of Physics and Technology , Dolgoprudny, , Russia

[21 ]Division of Epidemiology and Biostatistics, University of Illinois at Chicago School of Public Health , Chicago, , IL, 60612 USA

[22 ]Juvenescence Limited, Douglas, Isle of Man, UK

Author notes

Correspondence to: Morten Scheibye-Knudsen; email: mscheibye@ 123456sund.ku.dk

Article

Publisher ID: 101646

DOI: 10.18632/aging.101646

PMC ID: 6286828

PubMed ID: 30425188

SO-VID: ef7f9b6c-d2f2-460a-9841-b78d8b14208d

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 08 October 2018

Date accepted : 04 November 2018

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Most cited references 42

Antioxidants prevent health-promoting effects of physical exercise in humans.

Cellular Senescence: A Translational Perspective

Aging of blood can be tracked by DNA methylation changes at just three CpG sites

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Cited by 13

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