Speeding up Drug Discovery for Geroprotectors

I'm far from convinced it is the best path forward in the matter of treating aging, but much of the research community is focused on finding drugs that can alter patterns of gene expression and the operation of signaling pathways that tend to change with aging in order to run in a more youthful manner. There are hundreds of potential candidates at this point, described in the geroprotectors database; things like metformin and rapamycin are in that list. This seems to me to be putting the cart before the horse, in that these changes are not the cause of aging but rather downstream consequences of cell and tissue damage. It is possible that some benefit can be obtained by forcing a more youthful function of cells despite the underlying damage that they are reacting to, but trying to coax a damaged machine into better function without actually repairing that damage tends to be an expensive exercise in obtaining only marginal results. Most of the medicine for age-related disease created over the past century establishes the bounds of the possible here, as next to none of it touches on the root causes of aging. You can slow things down, or make things somewhat better, but you can't produce the large improvements that would be possible by reverting the damage that causes aging. Is that worth the effort now, at a time when addressing the root causes of aging is actually plausible? I'd say no. Pursue the better strategy instead, that outlined by the SENS rejuvenation research program, a focus on repair of fundamental damage rather than trying to compensate for it.

A significant rise in the proportion of seniors worldwide is underway, resulting in increasing rates of chronic, debilitating disease and long term residential care, shrinking the supporting workforce, and threatening to sink current health care systems. Prevention will be crucial moving forward. If aging can be delayed and diseases prevented, productive years can be extended and retirement age redefined. Anti-aging therapies have been sought since the dawn of human civilization, but with the rise of modern biology, big data, and information sciences, intelligent approaches to geroprotector discovery may finally be within reach. The outward features of aging, including decline in function and rise in susceptibility to stress and disease, are associated with a set of structural and functional changes at the cellular level. While these changes vary by tissue, many are genetically regulated, and many genes mediating longevity, termed gerontogenes, have been identified. The identification of these genes and experimental manipulation of their products to extend lifespan in model organisms has bolstered the notion that aging is not just a natural process but a treatable disease and added credence to the movement to identify drugs or other factors that may also extend lifespan, or, more favorably, healthspan, in humans. These are termed geroprotectors.

There are now over 200 substances that have shown geroprotective effects in model organisms. Human-based studies, however, may turn out to be more productive. Several of the most promising attempts at developing geroprotectors have involved identifying FDA-approved drugs with life-extending qualities and repurposing them as geroprotectors for human use. These include rapamycin and metformin. However, a number of problems still hamper the widespread approval and use of these or other drugs for this purpose. Most notably, longevity is a difficult parameter to study in humans without large, longitudinal designs, and since these drugs would presumably be administered to aging but otherwise healthy individuals, the effect size would have to be substantial and side effects almost non-existent. In addition, the FDA does not consider aging an approved disease indication. At this time, no drug has sufficiently met these conditions, and new approaches to drug discovery - and drug repurposing - are needed.

The drug discovery process is slow and expensive, burdened by many projects that dead-end before clinical trial or fail thereafter. Improved prediction of drug performance prior to lengthy experimentation would cut waste. Vast datasets now exist that enable such prediction with the help of sophisticated computational methods. Two particularly valuable datasets in this respect are the literally millions of gene expression profiles stored in repositories and a number of increasingly diverse compound screening libraries. While gene expression data can be used to pinpoint target pathways for a particular disease, compound libraries can be screened for drugs that target these pathways. All of this can be done in silico, at relatively little cost. Recently, a method was developed that would do just this - capitalize on existing gene expression data and compound libraries to improve prediction of targeted drugs. The method involves the use of an algorithm termed Oncofinder. Oncofinder quantifies Pathway Activation Strength (PAS) in a given sample based on gene expression patterns relative to another sample. Thus PAS values can be computed for a disease state in comparison to a normal state, old versus young, or any other set of physiological conditions. Here, we used an aging-based extension of Oncofinder, known as GeroScope, in a search for novel geroprotective substances.

We first quantified activation of age-related pathways in hematopoietic and mesenchymal stem cells from "old" (vs "young") human donors. We then shortlisted substances predicted to best target those pathways, restore a "young" cellular profile, and extend viability. From that list, we proceeded to experimentally test the effects of each substance in human fibroblasts. The top geroprotector, in terms of performance in both enhancing viability and rejuvenation was PD-98059, a highly selective inhibitor of MEK1 and the MAP kinase cascade. MEK inhibition along with PI-3K inhibition has been shown to decelerate cellular senescence via the mTOR/S6 pathway, a known target for anti-aging interventions. Aside from PD-98059, most of the studied geroprotectors had effects on either cellular viability or senescence features.

Link: http://dx.doi.org/10.18632/aging.101047


Finally, someone showed that MEK and MAPK inhibitors can decelerate cell senescence in humans. Some of the cancer drugs can be effective geroprotectors. We need more information on the dosage.

Posted by: Natalie at September 29th, 2016 10:15 PM
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