Research: A new era for research into aging
eLife is publishing a special issue on aging, geroscience and longevity to mark the rapid progress made in this field over the past decade, both in terms of mechanistic understanding and translational approaches that are poised to have clinical impact on age-related diseases.
- Department of Laboratory Medicine and Pathology, University of Washington, United States
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, United States
Every major cause of death and disability in the developed world shares a greatest risk factor, and it is probably not what most people would think. Smoking, obesity, a sedentary lifestyle and drinking too much alcohol all contribute to disease: however, their contributions are small in comparison to the physiological changes that result from aging. Whether biological aging causes the many functional declines that occur with age, or just permits them, is perhaps open for debate, but there is no question that, for most of us, biological aging determines how and when we and our loved ones will get sick and die.
This connection between aging and disease has become particularly consequential during the COVID-19 pandemic, with the vast majority of severe cases and deaths occurring among the elderly. Given this obvious relationship, it is somewhat surprising how slowly the biomedical research community has come to appreciate the importance of biological aging in many of the disease processes under study. It is our hope that the articles in the eLife special issue on aging, geroscience and longevity will contribute to a greater appreciation and understanding of aging biology among the broader scientific community. A number of the authors of these articles also spoke at a recent eLife symposium on this topic.
Today, unfortunately, too many scientists study individual diseases without recognizing the impact of aging biology. It is still common, for example, to see research studies in cancer, neuroscience, metabolism and other fields where young animal models (such as 4–6 month old mice) are used to study disease processes that almost exclusively occur in old people. ‘Mice are not people’ is a standard refrain when explaining why so many preclinical therapies fail in human trials. Perhaps the mouse isn’t the problem. Failing to account for the physiological changes that occur during aging, both in mice and in people, may be a much bigger reason why so much preclinical research fails to translate to the clinic.
It is still common to see research studies in cancer, neuroscience, metabolism and other fields where young animal models are used to study disease processes that almost exclusively occur in old people.
Thinking about certain conserved molecular mechanisms as 'hallmarks' or 'pillars' of aging (Kennedy et al., 2014; López-Otín et al., 2013) has benefitted researchers within the field, and has also allowed scientists outside the field to begin to recognize how aging biology impacts on their own research. Many of these conserved mechanisms are studied in the papers in this special issue, including telomere attrition, mitochondrial dysfunction, cellular senescence, epigenetic alterations, stem cell exhaustion, genomic instability, and loss of proteostasis.
Another important advance in aging research has been the development of a concept called geroscience: researchers in this area seek to understand mechanistically how the hallmarks of aging cause age-related disease and functional decline (Sierra and Kohanski, 2017). The growth of the geroscience concept also reflects a recognition that aging research is much closer to clinical application than it was twenty years ago. Numerous interventions have been developed that target one or more of the hallmarks of aging in order to delay, or even reverse, age-related functional declines. In rodents, for example, it has been shown that the drug rapamycin can prevent age-related diseases and improve function in multiple aged tissues and organs. Now, in the eLife special issue on aging, An et al. report that rapamycin also works in the oral cavity and can reverse periodontal disease in mice (An et al., 2020). Other articles suggest translational strategies to target specific hallmarks of aging for intervertebral disc degeneration (Cherif et al., 2020) and age-related heart disease (Chiao et al., 2020). At the time of writing there are two review articles and more than 20 research articles in the special issue, and more will be added over time.
The future of aging research is brighter than ever before, and the pace of discovery is only increasing. We look forward to major breakthroughs over the next few years that will revolutionize the way we think about aging biology and have the potential to significantly impact human healthspan and longevity.
References
Article and author information
Author details
Publication history
Copyright
© 2021, Kaeberlein and Tyler
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,108
- views
-
- 349
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Research: A new era for research into aging
eLife 10:e65286.
https://doi.org/10.7554/eLife.65286
Further reading
-
- Cancer Biology
- Cell Biology
The endoplasmic reticulum (ER) is an essential sensing organelle responsible for the folding and secretion of almost one-third of eukaryotic cells' total proteins. However, environmental, chemical, and genetic insults often lead to protein misfolding in the ER, accumulating misfolded proteins, and causing ER stress. To solve this, several mechanisms were reported to relieve ER stress by decreasing the ER protein load. Recently, we reported a novel ER surveillance mechanism by which proteins from the secretory pathway are refluxed to the cytosol to relieve the ER of its content. The refluxed proteins gain new prosurvival functions in cancer cells, thereby increasing cancer cell fitness. We termed this phenomenon ER to CYtosol Signaling (or ‘ERCYS’). Here, we found that in mammalian cells, ERCYS is regulated by DNAJB12, DNAJB14, and the HSC70 cochaperone SGTA. Mechanistically, DNAJB12 and DNAJB14 bind HSC70 and SGTA - through their cytosolically localized J-domains to facilitate ER-protein reflux. DNAJB12 is necessary and sufficient to drive this phenomenon to increase AGR2 reflux and inhibit wt-p53 during ER stress. Mutations in DNAJB12/14 J-domain prevent the inhibitory interaction between AGR2-wt-p53. Thus, targeting the DNAJB12/14-HSC70/SGTA axis is a promising strategy to inhibit ERCYS and impair cancer cell fitness.
-
- Cancer Biology
- Cell Biology
DNA base lesions, such as incorporation of uracil into DNA or base mismatches, can be mutagenic and toxic to replicating cells. To discover factors in repair of genomic uracil, we performed a CRISPR knockout screen in the presence of floxuridine, a chemotherapeutic agent that incorporates uracil and fluorouracil into DNA. We identified known factors, such as uracil DNA N-glycosylase (UNG), and unknown factors, such as the N6-adenosine methyltransferase, METTL3, as required to overcome floxuridine-driven cytotoxicity. Visualized with immunofluorescence, the product of METTL3 activity, N6-methyladenosine, formed nuclear foci in cells treated with floxuridine. The observed N6-methyladenosine was embedded in DNA, called 6mA, and these results were confirmed using an orthogonal approach, liquid chromatography coupled to tandem mass spectrometry. METTL3 and 6mA were required for repair of lesions driven by additional base-damaging agents, including raltitrexed, gemcitabine, and hydroxyurea. Our results establish a role for METTL3 and 6mA in promoting genome stability in mammalian cells, especially in response to base damage.
