Using Age-Related Gene Expression Changes to Search for Drugs to Slow Aging

Gene expression is the complex, dynamic process by which proteins are produced from their genetic blueprints. It changes constantly due to a shifting pattern of epigenetic decorations attached to DNA. Targeting gene expression changes that take place with age is the path advocated by the minority of researchers who believe that aging is an evolved program, an adaptation in which the damage and decline is selected for. They should favor the sort of work noted here, in which the epigenetic changes of aging are used to steer screening for drug candidates, in search of compounds likely to work in similar ways to metformin, mTOR inhibitors, aspirin, and other existing drugs shown to modestly slow aging in animal studies. There is a great deal of difference in size and reliability of effects between just the three mentioned above, and it isn't at all clear whether or not they are representative of other compounds waiting to be discovered.

If, as the majority of the research community believes, aging is not programmed, not directly selected, and is caused by an accumulation of forms of unrepaired cell and tissue damage, then epigenetic change with aging is a reaction rather than a cause. It is a downstream consequence of the real issues. Adjusting specific gene expression levels should have only small effects on the course of aging because the underlying damage remains to cause all of its other failures and harms. This is why I favor the SENS rejuvenation biotechnology approach over the popular work on mTOR inhibitors and the like - the research community must target the root causes rather than later consequences if the goal is meaningful gains in health and life span.

Pharmacological intervention can extend animal lifespan. The DrugAge database reports drug-induced lifespan extensions - up to 1.5-fold for C. elegans, 1.1-fold for D. melanogaster, and 31% for M. musculus. Some of these chemicals may mimic the effects of dietary restriction (DR). For example, resveratrol, which induces a similar gene expression profile to dietary restriction, can increase lifespan of mice on a high-calorie diet, although not in mice on a standard diet. Rapamycin, directly targets the mTORC1 complex, which plays a central role in nutrient sensing network and has an important role in lifespan extension by DR. Rapamycin extends lifespan by affecting autophagy and the activity of the S6 kinase in flies. However, it can further extend the fly lifespan beyond the maximum achieved by DR, suggesting that different mechanisms might be involved. Nevertheless, the mechanisms of action for most of the drugs are not well known.

Several studies have taken a bioinformatics approach to discover drugs that could extend lifespan in model organisms. For instance, the Connectivity Map, a database of drug-induced gene expression profiles, has been used to identify DR mimetics, and found 11 drugs that induced expression profiles significantly similar to those induced by DR in rats and rhesus monkeys. Although previous studies tried to discover drugs that can affect ageing, they all focus on genes or drugs related to lifespan regulation. The role of these drugs in promoting healthy ageing in humans is still an open question. In this study, using gene expression data for human brain ageing, we aimed to discover not only new pro-longevity drugs but also those that can improve health during ageing. The biological processes showing a change in expression include pathways related to synaptic and cognitive functions as well as proteostasis, suggesting gene expression changes in the ageing brain could be used as a surrogate to find drugs to target detrimental effects.

Using multiple gene expression datasets from brain tissue, taken from patients of different ages, we first identified the expression changes that characterise ageing. Then, we compared these changes in gene expression with drug perturbed expression profiles in the Connectivity Map. We thus identified 24 drugs with significantly associated changes. Some of these drugs may function as anti-ageing drugs by reversing the detrimental changes that occur during ageing, others by mimicking the cellular defense mechanisms. The drugs that we identified included significant number of already identified pro-longevity drugs, indicating that the method can discover de novo drugs that meliorate ageing. The approach has the advantages that, by using data from human brain ageing data it focuses on processes relevant in human ageing and that it is unbiased, making it possible to discover new targets for ageing studies.

Link: https://doi.org/10.1111/acel.12819

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