The largest risk factor for death by cancer, Alzheimer’s Disease, and even cardiovascular disease, is aging; outstripping the influence of diet, diabetes, tobacco and ApoE, literally, by orders of magnitude. Clearly, understanding the processes that modulate the rate at which we age stands to have a profound effect on disease incidence and the health of our aging society. In recent years it has become increasingly apparent that mitochondrial dysfunction plays a central role in the aging process (1).
My laboratory exploits the nematode Caenorhabditis elegans as a facile model organism to investigate aging and, specifically, the role mitochondrial dysfunction plays in this process. The primary focus of my group is on a class of long-lived C. elegans called the Mitochondrial (Mit) mutants (2-8). These animals contain one of several mutations in their mitochondrial electron transport chain (ETC) that paradoxically lengthen life. Life extension following ETC disruption has also been observed in other species, including mice. We aim to understand how such life extension unfolds. Several areas of research related to Mit mutants are ongoing in the lab.
(i) My group spent several years establishing novel gas chromatography/mass spectrometry (GC-MS) based techniques to map the metabolism of long-lived mitochondrial mutants (6, 8). We discovered that Mit mutants uniquely generate several metabolic end products that appear to act as signaling molecules in their own right (2). In fact, these molecules are closely related to another group of signaling molecules in humans called oncometabolites that target enzymes belonging to the a-ketoglutarate-dependent hydroxylase family and are involved in the etiology of some cancers (4). Currently we are using a variety of techniques that span chemistry, biochemistry and genetics, to explore how the unique metabolic profile of Mit mutants leads to their life extension. We are actively pursuing members of the large a-ketoglutarate-dependent hydroxylase family, since these proteins control a diverse range of processes including epigenetic programing, response to hypoxia and nucleic acid repair, all of which are processes known to be involved in the life extension of Mit mutants (5).
(ii) We previously found that p53 is activated in Mit mutants and that it too is involved in the longevity specification of these animals. Surprisingly, we have found no evidence for nuclear DNA damage in Mit mutants. Instead, in our most recent work we have discovered a novel mitochondrial-nucleus-ribosome signaling axis that acts to control lifespan. We are actively dissecting the elements of this pathway.
(iii) We have uncovered a new retrograde signaling pathway in Mit mutants that appears to be a novel branch of the surveillance and innate immunity defense (cSAID) pathway. This signaling pathway works in parallel to the well described ATFS-1/SKN-1 (NRF-2) pathway of cSAID, and both pathways literally counterbalance each other such that upregulation of one pathway leads to a reduction in the other, and vice versa. Using the powerful genetic toolbox of C. elegans we have identified several new genes that map to this new signaling cascade.
(iv) We recently screened over 500 transcription factors for their involvement in Mit mutant life extension (5). We identified TAF-4, a component of the basal transcription machinery, as a specific factor essential for Mit mutant life extension. We are now using a variety of approaches including RNA-seq, and structure-function analyses to define how this protein works to specify Mit mutant longevity.
Finally, my group has recently expanded into a new drection and we have been using systems biology tools in a novel approach to understand mechanisms of cellular aging. As a test-bed, we have focused on the single-celled yeast Saccharomyces cerevisiae. We have been exploiting in silico metabolic models that were originally developed by the chemical engineering field to identify metabolic states are associated with increased replicative lifespan in S. cerevisiae (which is the equivalent of extended lifespan in higher organisms). These studies are exciting for the possibilities they now afford in being able to engineer aging rate.
1. Mishur RJ, Khan M, Munkacsy E, Sharma L, Bokov A, Beam H, Radetskaya O, Borror M, Lane R, Bai Y, Rea SL. Mitochondrial metabolites extend lifespan. Aging Cell. 2016;15(2):336-48. doi: 10.1111/acel.12439. PubMed PMID: 26729005.
2. Munkácsy E, Khan MH, Lane RK, Borror MB, Park JH, Bokov AF, Fisher AL, Link CD, Rea SL. DLK-1, SEK-3 and PMK-3 Are Required For The Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans. PLoS Genetics. 2016;(accepted for publication).
3. Lane R, Hilsabeck T, Rea SL. The Role of Mitochondrial Dysfunction in Age-related Diseases. Biochim Biophys Acta. 2015 Nov;1847(11):1387-400. doi: 10.1016/j.bbabio.2015.05.021. Epub 2015 Jun 4. Review. PubMed PMID: 26050974.