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Signaling from dysfunctional mitochondria induces a distinct type of senescence

Finding provides alternative explanation for the free-radical theory of aging and suggests new role for mitochondria in affecting physiology

Buck Institute for Research on Aging


IMAGE: These are fat biopsies stained for senescence (blue). Left: Normal wild type mice, aged 8 months Right: Mouse model of mitochondrial progeria view more

Credit: Akos Gerencser, PhD, Buck Institute

Buck Institute faculty Judith Campisi, PhD, says age researchers need to stop thinking of cellular senescence, now accepted as an important driver of aging, as a single phenotype that stems from genotoxic stress. Research from her lab reveals that cellular senescence, a process whereby cells permanently lose the ability to divide, is also induced by signaling from dysfunctional mitochondria - and that the arrested cells secrete a distinctly different "stew" of biologically active factors in a process unrelated to the damaging free radicals that are created in mitochondria as part of oxygen metabolism. The results are published in Cell Metabolism.

"We don't yet know how much this process contributes to natural aging," said Campisi, adding that those studies are currently underway. "But we do think the findings are important in addressing mitochondrial diseases, and those age-related diseases, such as some forms of Parkinson's, which involve mitochondrial dysfunction."

The discovery was unexpected and was made by postdoctoral fellow Christopher Wiley, PhD, who (in collaboration with Eric Verdin, PhD, from the Gladstone Institute) was eliminating sirtuins, a class of proteins long linked to longevity, one by one in human cell cultures. "The senescent phenotype only occurred when we eliminated the mitochondrial sirtuins," said Wiley. In addition, Wiley saw that the senescent cells secreted a different SASP (senescence-associated secretory phenotype) than expected - one that lacks the IL-1-dependent inflammatory arm - a major factor in the SASP originally identified in the Campisi lab in 2008. The authors dubbed this new phenomenon MiDAS - mitochondrial dysfunction-associated senescence.

Along with identifying MiDAS, Wiley also found that mitochondrial dysfunction upset the balance of NAD+ (an enzyme that is a co-factor for sirtuins), which arrested cell growth and prevented the IL-1-associated SASP. "The NAD+ balancing act happens outside the mitochondria in the cytoplasm of the cell," said Wiley. "This really highlights a signaling role for mitochondria, something understudied in the context of disease. And it identifies a new type of SASP, underscoring the existence of different types of senescence."

Wiley also identified the MiDAS SASP in mice genetically engineered to develop progeria in response to mitochondrial mutations, which causes rapid aging. The MiDAS SASP suppressed adipogenesis, which plays a vital role in metabolism and the creation of fat cells. He says the work provides a link to lipodystrophy, a medical condition characterized by abnormal or degenerative conditions involving fat tissue, adding that early HIV drugs (which are still being used in third world countries) deplete mitochondrial DNA and that patients receiving the drugs often show a particular loss of subcutaneous fat, especially in their face.

"For any disease that has a mitochondrial component this research adds a potential explanation for the real driver of the dysfunction -- and it's not free radicals, which we ruled out in our study" said Campisi. "Our finding suggest a new role for mitochondria when it comes to affecting physiology."


Citation: DOI: 10.1016/j.cmet. 2015.11.011 Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

Other Buck researchers involved in the study include Michael C. Velarde, Pacome Lecot, Su Liu, Ethan A. Sarnoski, Adam Freund, Sonnet S. Davis, Arvind Ramanathan, and Akos A. Gerencser. Collaborators from the Gladstone Institute include Eric Verdin, Kotaro Shirakawa and Hyung W. Lim. The work was funded by NIH grants T32-AG00266, R37-AG009909, K-99-AG041221 and fellowships from the American Federation of Aging Research and the SENS Research Foundation and ExploRA', PULSE and CROUS from France.

About the Buck Institute for Research on Aging

The Buck Institute is the U.S.'s first independent research organization devoted to Geroscience - focused on the connection between normal aging and chronic disease. Based in Novato, CA, The Buck is dedicated to extending "Healthspan", the healthy years of human life and does so utilizing a unique interdisciplinary approach involving laboratories studying the mechanisms of aging and those focused on specific diseases. Buck scientists strive to discover new ways of detecting, preventing and treating age-related diseases such as Alzheimer's and Parkinson's, cancer, cardiovascular disease, macular degeneration, osteoporosis, diabetes and stroke. In their collaborative research, they are supported by the most recent developments in genomics, proteomics, bioinformatics and stem cell technologies. For more information:

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