Metabolism and Aging
Over the last decade, we have pursued a more fundamental understanding of metabolism and aging in collaboration with biologists at MGH through two methods:
- High Throughput Screens yield insights through discovery science and pathway mapping.
- Mathematical modeling of aging and demography explains prior results and generates new hypotheses and predictions.
Selected impacts to date include:
- Identifying conserved genes that regulate fat storage (doi: 10.1016/j.celrep.2017.06.068) and reproductive senescence (doi: 10.1371/journal.pgen.1004752).
- Elucidating how a common drug taken by diabetics, metformin, kills cancer cells and extends lifespan, while identifying new potential drug targets (doi: 10.1016/j.cell.2016.11.055).
- Characterizing the role of stress resistance pathways in longevity.
- Mapping out cellular and organismal pathways, such as insulin signalling, that have large effects on rate of aging and longevity.
Aging appears to be a consequence of damage accumulation, which arose because of the evolution of a fixed body plan that does not completely turn over, or turn over at a high enough rate. This fixed body plan appears to have evolved in a similar time frame as sexual reproduction. Indeed, my (presently unpublished) model of aging predicts a start time for aging that is approximately puberty, differs between men and women, and tracks changes in secular trends over the last century, all while only using adult mortality curves as an input.
Aging drugs are coming -- and we have an ethical responsibility to ensure they are not only for the few or the wealthy. Healthspan enhancing drugs, while not impacting aging per se, would allow more of us to live out our "natural" lifespans in relative health.
I suspect that thermo-neutral temperature plays a more important role in sleep, and thus executive function, health, and lifespan, than we have realized to date. If true, a natural consequence is that we could enhance human capital, and likely economic growth, by ensuring that all humans, especially children, have thermo-neutral sleep environments.
Peer Reviewed Publications
Webster CM, Pino EC, Carr CE, Wu L, Zhou B, Kacergis MC, Curran SP, Soukas AA. Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival. Cell Reports. 18 July 2017, 20(3):627–40 doi:10.1016/j.celrep.2017.06.068 OpenAccess
L Wu, M Li, N Oshiro-Rapley, B Zhou, CM Webster, F Mou, MC Kacergis, ME Talkowski, CE Carr, B Zheng, AA Soukas. An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer. Cell 167(7):1705-18, 15 Dec 2016; doi: 10.1016/j.cell.2016.11.055, PMC5390486 (2017/12/15).
Wang MC, Oakley HD, Carr CE, Sowa JN, and Ruvkun G. Gene pathways that delay Caenorhabditis elegans reproductive senescence. PLoS Genetics 10(12): e1004752 (2014) doi: 10.1371/journal.pgen.1004752 OpenAccess
Sasaki T, Lian S, Qi J, Bayliss PE, Carr CE, Johnson JL, Guha S, Kobler P, Catz SD, Gill M, Jia K, Klionsky DJ, Kishi S. Aberrant Autolysosomal Regulation Is Linked to The Induction of Embryonic Senescence: Differential Roles of Beclin 1 and p53 in Vertebrate Spns1 Deficiency. PLoS Genetics 10(6): e1004409. doi:10.1371/journal.pgen.1004409OpenAccess.
Pino L, Webster C, Carr CE, Soukas AA. Biochemical and high throughput microscopic assessment of fat mass in Caenorhabditis elegans. J Vis Exp 2013 Mar 30 (73) doi:10.3791/50180.
Shore DE, Carr CE, Ruvkun G (2012) Induction of Cytoprotective Pathways Is Central to the Extension of Lifespan Conferred by Multiple Longevity Pathways. PLoS Genet 8(7): e1002792. doi:10.1371/journal.pgen.1002792
Koshimizu E, Imamura S, Qi J, Toure J, Valdez DM Jr, Carr CE, Hanai J, and Kishi S. 2011 Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model. PLoS ONE 6(3): e17688. doi:10.1371/journal.pone.0017688. PMCID: PMC3068137
O’Rourke E, Soukas A, Carr CE, and Ruvkun G. C. elegans Major Fats are stored in vesicles distinct from lysosome-related organelles. Cell Metabolism 4 Nov 2009 10(5):430-435; doi:10.1016/j.cmet.2009.10.002.
Soukas AA, Kane EA, Carr CE, Melo JA, and Ruvkun G. Caenorhabditis elegans Rictor/TORC2 regulates fat metabolism and lifespan in a diet-dependent manner. Genes & Development (2009) 23:496-511; doi: 10.1101/gad.1775409.
Samuelson AV, Klimczak RR, Thompson D, Carr CE, Ruvkun G. Indentification of C. elegans genes regulating longevity using enhanced RNAi-sensitive strains. Cold Spring Harb Symp Quant Biol 2007 72:489-97, doi: 10.1101/sqb.2007.72.068.
Samuelson AV, Carr CE, and Ruvkun G. Gene activities that mediate increased lifespan of C. elegans insulin-like signaling mutants. Genes & Development 2007 Nov 15; 21(22):2976. doi: 10.1101/gad.1588907.