Most Small Molecules that Influence Life Span in Model Organisms Also Influence Expression of Extracellular Matrix Genes
An interesting observation is discussed in this open access paper, which is that most small molecule compounds that extend life in short lived species also change the expression of extracellular matrix genes. The majority of such compounds are thought to extend life by provoking some of the same stress response mechanisms as calorie restriction, heat shock, and other common stressors, resulting in improved cell maintenance and thus improved cell and tissue function. Why do they also lead to changes in cellular activity relating to the maintenance of the extracellular matrix? A detailed answer to that question may emerge at some point, but cellular metabolism and its interaction with aging are very complex, slow-moving areas of study. Manipulation of metabolism to slow aging is a part of the field in which interventions are found by screening, none are fully understood, and none have interestingly large effects in long-lived species such as our own.
A few geroprotective drugs exist that postpone age-related diseases. For instance, the anti-diabetes drug metformin reduces age-related chronic diseases and mortality from all causes. Ongoing clinical trials on geroprotective drugs or compounds include the anti-diabetic drugs metformin and acarbose; mTOR-inhibiting and immunosuppressant drug rapamycin; natural compounds resveratrol and urolithin A; and nicotinamide adenine dinucleotide precursors NR and NMN. One primary outcome measure used in the aforementioned clinical trials for metformin and acarbose is the restoration from an "old" to a "youthful" gene expression signature. Therefore, we reasoned that cross-comparing youthful expression signatures against expression profiles elicited by small molecules could identify geroprotective compounds.
A key signature of aging is the continuous decline of collagen and cell adhesion gene expression accompanied with an increase in matrix metalloproteinase expression. Gene expression ontologies of extracellular matrix (ECM) genes have been associated with healthy aging in humans. The ECM not only embeds cells and tissues but also provides instructive cues that change cellular function and identity. For instance, placing old cells into a "young" ECM rejuvenates senescent cells or stem cells and even reprograms tumor cells. Moreover, collagen homeostasis is required and sufficient for longevity in Caenorhabditis elegans. Chondroitin biosynthesis and TGFβ pathway are frequently enriched in C. elegans longevity drug screens. Collectively, these functionally implicated genes are all members of the matrisome.
To harness this observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a "youthful" matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for Caenorhabditis elegans longevity. With this reporter, we were able to eliminate false-positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach - employing extracellular matrix homeostasis - facilitates the discovery of pharmacological interventions promoting healthy aging.