For many years, it has been believed that the aging process is inevitable and that age-related diseases cannot be prevented or reversed. For example, the US Food and Drug Administration (FDA) does not recognize aging as an indication for drug approval because there are no markers to determine whether possible treatments have a significant impact on the hallmarks of aging.
The field of geroscience aims to find ways to change this by delaying the onset of age-related diseases or by extending the life span. On May 19, 2021, experts in geroscience met virtually at a symposium of the New York Academy of Sciences. Presentations and discussions with experts in the field showed that remarkable advances have been made in understanding the mechanisms underlying biological aging. Those mechanisms contribute to the vulnerability of older adults. The presentations focused identifying biomarkers of aging and on the search for interventions to prevent and treat age-related diseases.
Perspectives from this meeting were published in a report.
An Abridged Glossary
Senescent cells: These are old cells with irreversibly damaged DNA; they strongly resist apoptosis. Thus, they are not eliminated and continue to secrete pathogenic proinflammatory molecules.
Senolytics: This is a class of compounds that promote the removal of senescent cells from the body.
Autophagy: This is a process that promotes protein degradation, which is attenuated with aging and that impedes the aggregation of proteins harmful to cell function, particularly those of the central nervous system.
Proteostasis: This is the dynamic regulation of protein homeostasis.
Epigenetics: This is the field of biology that studies phenotype changes that are not caused by changes in DNA sequencing and that continue to affect cellular division.
Metabolome: This refers to small molecules that make up the building blocks of all organismal features, from cell membranes to metabolic cycles to genes and proteins.
Translational research: This involves applying primary research results to clinical research, and vice versa.
Possible Research Topics
Senescence not only occurs with age but also drives aging. At the meeting, evidence was provided that senescent cells may exacerbate the clinical course of older adults in cases of infections (eg, COVID-19) as they lead to cytokine storms. Experiments on old mice that have undergone genetic modification of senescent cells or the administration of “senolytic cocktails” composed of dasatinib plus quercetin protected the animals from the effects of viral infections. This finding corroborates the idea that factors involved in biological aging increase vulnerability and could be modified through treatment.
Alzheimer’s disease is an example of the effects of cellular senescence. Senescent cells develop a senescence-associated secretory phenotype that can be toxic to neighboring healthy cells and can allow senescence to propagate within tissues. This effect makes Alzheimer’s disease an essential focal point when studying the use of senolytics. In addition, agents that stimulate autophagy may be of interest for treating degenerative diseases.
Assessing Therapeutic Effects
It may be possible to assess the therapeutic effects of drug candidates using the following biomarkers.
Growth hormone and type 1 insulin-like growth factor (IGF-1): Older adults are often prescribed growth hormone. However, recent data suggest that doing so is not advantageous to this patient population because it antagonizes proteostasis and other cell maintenance mechanisms in older age. Experimental studies and studies conducted on centenarians suggest that low growth hormone and IGF-1 levels contribute to longevity and may be therapeutic biomarkers.
Epigenetics: DNA methylation is a method that offers an “epigenetic clock” to compare biological age with chronologic age. Higher epigenetic age was associated with increased mortality risk, breast cancer, and nonalcoholic fatty liver disease. Therefore, it could also be a therapeutic biomarker.
Metabolomics: Studying metabolomes facilitates the identification of the link between genetic polymorphisms and longevity, as most polymorphisms explain <0.5% of longevity variations.
New translational strategy: It is common practice to treat each age-related disease individually. An alternative strategy would be to target the hallmarks of biological aging to prevent these diseases from developing. The rate of biological aging correlates with the speed of damage accumulation at the macromolecular, organelle, and cellular levels. It also affects the capacity of the body to repair this damage. The assessment of biomarkers would make possibile research into the effects of short- and long-term treatments that minimize damage and enhance resilience related to diseases common with aging.
New Translational Research
The report highlights two translational research models: the in-depth study of centenarians, and the analysis of how immune aging makes older adults vulnerable to COVID-19. The impact of impaired immunity on aging became particularly evident during the pandemic. However, to home in on immunity as a therapeutic target and to better understand immune resilience, the specific nature of immune and biological deficits still need to be defined.
Metformin is among the therapeutic agents under investigation in cutting-edge clinical research. Its effect on aging will be studied in the Targeting Aging with Metformin (TAME) clinical trial. This trial is the first to study aging outcomes. The goal is to create a regulatory framework that future therapies can follow to achieve FDA approval.
There are three promising therapeutic platforms among the cutting-edge research studies. The first aims to produce adenosine triphosphate, levels of which decline dramatically with aging. The second aims to promote autophagy to remove cellular waste to treat neurodegenerative diseases. The third reprograms the epigenome to a younger state.
Research on mitochondrial dysfunction is relevant because it is highly involved in age-related diseases. Mitochondrial-derived peptides could potentially serve as biomarkers of mitochondrial function in aging studies and become promising therapeutic targets in age-related diseases. One of these peptides, humanin, has been demonstrated to exert protective effects on the heart, brain, and liver. Researchers observed that mitochondrial proteins are age-dependent and are suppressed by growth hormone and IGF-1. They also found that humanin levels are correlated with endothelial function. Data from animal studies have shown that sustained humanin levels are positively linked to longevity; these findings are mirrored in data from centenarians and their offspring, who have higher levels of humanin.
The formation of a Translational Geroscience Network composed of several scientists from various institutions should accelerate the application of this understanding. Despite the ongoing investigational and clinical studies, senolytics should not be regarded as extending life span or treating certain conditions, because their full safety profiles have not yet been elucidated.
Geroscience faces challenges in dealing with age-related problems. It is hoped that these challenges will be overcome through investigational and clinical studies on the mechanisms involved in aging. In-depth study of the interactions of underlying mechanisms of aging are needed to answer the following questions:
Is there a hierarchical relationship among these mechanisms?
Are there organ or cell-type differences in the interactions among these mechanisms?
Is it possible to achieve a synergistic effect through combined interventions targeting several of the processes that drive aging?
It is complicated, but researchers are starting to see the light at the end of the tunnel.
This article was translated from the Medscape Portuguese edition.
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