Faculty

My long-term research goal is to understand (i) how the nervous system retains its function and integrity throughout its lifespan and (ii) how it affects organismal aging and health. My current research goals are to investigate:i) how aging neurons regulate mitochondrial dynamics and localization in response to local demand and injury; ii) how mitochondria control nuclear gene expression in two key conditions, including aging and injury; iii) how mitochondria respond to environmental stress and affect organismal aging and health; iv) how mitochondria stress in the nervous system modulate organismal lifespan and healthspan. We utilize the nematode C. elegans as a powerful genetic and in vivo model to answer these questions.

We have published over 300 publications (most of them original research publications) with an overall h-index of 99. I have used animal models to discover biological pathways and genes that regulate the rate of aging and/or become causal to aging. Although aging is highly complex, my team has made significant advances in better understanding the biology of aging by understanding the cellular and molecular processes. As my team learns more about these biological processes, experiments can be designed to better understand when and how pathological changes begin with aging providing important clues toward developing the timing and type of interventions to prevent or treat disease. Five areas are covered on some of the discoveries and implications: (1) apoptosis and aging; (2) mitochondria and aging; (3) autophagy and aging; (4) iron and aging; and (5) preclinical and clinical studies to extend health span.

1) Apoptosis and Aging. We were the first to document the existence of apoptosis (programmed cell death) in muscle, brain and heart tissues with old age. For example, we showed a loss of myocytes in the aging heart due to Mt-mediated apoptosis. Our study was the first to report cytochrome c release from the mitochondria and alterations in Bcl-2 with age in vivo, providing a potential mechanism for the increase in apoptosis seen in the aging heart. Furthermore, we found similar mechanisms in muscle and brain tissues and were also the first to provide evidence that intervention such as caloric restriction (CR) and exercise can attenuate several mechanisms of apoptosis. (a) Phaneuf S, and Leeuwenburgh C, Cytochrome c release from mitochondria in the aging heart: a possible mechanism for apoptosis with age. Am J Physiol Regul Integr Comp Physiol. 2002; (b) Shelke RR, and Leeuwenburgh C, Lifelong CR increases expression of apoptosis repressor with a caspase recruitment domain (ARC) in the brain. FASEB J. 2003; (c) Dirks AJ, and Leeuwenburgh C, Aging and lifelong calorie restriction result in adaptations of skeletal muscle apoptosis repressor, apoptosis-inducing factor, X-linked inhibitor of apoptosis, caspase-3, and caspase-12. Free Radic Biol Med; and (d) Someya et al. Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis Proc Natl Acad Sci USA. 2009.

2) Mitochondria and Aging. We found that Mt mutations drive mammalian aging and determined that Mt sirtuin-3 (Sirt3) is essential for maintaining Mt redox status. In 2005 we published a paper in Science (Kujoth, Science 2005) that reported our use of transgenic mice to show that for the first time that accumulating mtDNA mutations promotes apoptosis and is a central mechanism that drives mammalian aging. Our investigative teams showed that mice expressing a proofreading-deficient version of the Mt DNA polymerase g (POLG) accumulate mtDNA mutations while simultaneously displaying characteristics of accelerated aging. Accumulation of mtDNA mutations was also associated with the induction of apoptosis, particularly in tissues characterized by rapid cellular turnover. In addition, we published a paper in the journal Cell entitled, “Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss (AHL) under caloric restriction” (Someya, Cell 2010). This paper reported for the first time that the Mt sirtuin (Sirt3) had an important role in maintaining an important physiological function (hearing loss) with aging. It was already known from our previous studies that CR extends the lifespan and health span of a variety of species. What was unknown is whether Sirt3 slows the progression of AHL, a common age-related disorder. Several studies showed that that CR reduces oxidative DNA damage in multiple tissues and prevents AHL in wild-type mice but fails to modify these phenotypes in mice lacking the –mitochondrial- deacetylase Sirt3, a member of the sirtuin family. Collectively, these findings identify for the first time that Sirt3 plays an essential role in enhancing the Mt glutathione antioxidant defense system during CR and shows that Sirt3-dependent Mt adaptations are a central mechanism that slows aging in mammals. (a) Kujoth et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 2005 (b) Someya et al. Sirt3 mediates reduction of oxidative damage and prevention of AHL under CR. Cell 2010 (c) Hiona et al. Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice, PLOS One. 2010; and (d) Leeuwenburgh C and Prolla T. Genetics, redox signaling, oxidative stress, and apoptosis in mammalian aging. Antioxid Redox Signal. 2006.

3) Autophagy and Aging. We were the first to examine the molecular mechanisms of autophagy decline with aging (i.e., loss of LC3, LAMP-2, Atg4B, and Beclin-1 with and without transfection technology) and the ability of exercise or CR to stimulate autophagy. We found that LC3 gene and protein expression pattern as well as LAMP-2 gene expression, both downstream regulators of autophagy contributed to an age-related decline in autophagic degradation. Moreover, calorie restriction mediated beneficial effects by stimulating autophagy in the heart, indicating the potential for cardioprotective therapies. We documented that autophagy is limited in aged liver exposed to ischemia reperfusion injury. Loss of Atg4B in livers of old mice increases their sensitivity to I/R injury and therefore increasing autophagy might ameliorate liver damage and restore Mt function after I/R. Indeed, overexpression of either Atg4B or Beclin-1 recovered Atg4B, increased autophagy, blocked the onset of the Mt permeability transition, and suppressed cell death after I/R in old hepatocytes. We also extended these mechanistic finding to several human studies investigating PAD (ischemia/reperfusion highly prevalent), patients undergoing mechanical ventilation (inactivity of the diaphragm) during surgery, and in older obese subjects (inactivity causing the lack of autophagy). (a) Wohlgemuth SE, et al. Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and lifelong exercise. Exp Gerontol. 2010; (b) Wohlgemuth et al. An exploratory analysis of the effects of a weight loss plus exercise program on cellular quality control mechanisms in older overweight women. Rejuvenation Res. 2011; (c) Wang JH et al. Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice. Gastroenterology. 2011; and (d) Mankowski RT et al. Intraoperative hemidiaphragm electrical stimulation reduces oxidative stress and upregulates autophagy in surgery patients undergoing mechanical ventilation: exploratory study. J Transl Med. 2016.

4) Iron and Aging. In model systems of aging (mammals and C. elegans) we have unequivocally shown that cellular and Mt iron accumulate with age and alters Mt function. These finding provide a potential target for future interventions. In the Journal Aging Cell we showed in animals that an accumulation of Mt iron increased the susceptibility of Mt permeability transition pore opening, Mt dysfunction and oxidative damage, thereby enhancing the susceptibility to apoptosis. We also investigated iron accumulation in C. elegans (well-established model organism for aging research). Novel discoveries were made related to the Mt iron-sulfur cluster assembly protein ISCU-1/ISCU with age. We also investigated zinc transporter such as ZIP14 (slc39a14), which can also function as an iron transporters and their response-adaptations to pro-inflammatory stimuli, e.g., interleukin-6. More recently, we extended these mechanistic findings to further investigate muscle pathology (iron deregulation, Mt biology and muscle biology) in humans of different (low- vs. high-functioning) functional status. In humans, we showed marked disruption in several muscle iron-transport proteins such transferrin receptor-1 (TfR1), Zip14, mitoferrin, and frataxin. We very recently received an impact score of 13 and percentile of 1% on the NIH proposal, “Functional Decline in Low-Functioning Older Adults; Role of Iron Dysregulation.” This NIH grant is funded and has started (9/1/2022-6/30/2027; $2,978,789). This is a cross-sectional as well as a longitudinal study with 120 older participants to investigate for the first time systemic, cellular, and Mt metals (iron, copper, zinc) deregulation (transport, import, export) with aging. Again this testified my ability to translate animal studies to human clinical studies to help aid the discovery of potential biological targets and future interventions. (a) Seo AY et al. Mitochondrial iron accumulation with age and functional consequences. Aging Cell. 2008; (b) Sheng Y et al. A novel role of the mitochondrial iron-sulfur cluster assembly protein ISCU-1/ISCU in longevity and stress response. Geroscience. 2021; (c) Aydemir TB et al. Aging amplifies multiple phenotypic defects in mice with zinc transporter Zip14 (Slc39a14) deletion. Exp Gerontol. 2016; and (d) Picca A et al. Altered expression of mitoferrin and frataxin, larger labile iron pool and greater mitochondrial DNA damage in the skeletal muscle of older adults. Cells. 2020.

5) Preclinical and Clinical Studies to Extend Health Span. My most recent chapter (over the past 12 years) has focused on translating basic finding discoveries from the biology of aging and findings from preclinical intervention into human clinical trials to improve health span. In a team science approach with the University of Northwestern, University of Kentucky we are testing compounds (i.e., resveratrol, NAD+ precursors, epicatechins, curcumin, urolithin A, beet juice) and pharmacological agents (metformin, rapamycin, testosterone, telmisartan, losartan) that target genes such as sirtuins, AMPK, mTOR, PGC-1α and nitric oxide production. We have clinical studies ongoing or completed using compounds to target these master metabolic genes such as sirtuins (Sirt1 and Sirt3), mTOR, metabolic Mt biogenesis gene (PGC1a), AMPK, and compounds to increase the levels of intracellular NAD+ (which declines with age). Completed and ongoing clinical trials are:

• Resveratrol to Enhance Vitality and Vigor in Elders: The REVIVE Trial; • Nicotinamide riboside as an Enhancer of Exercise Therapy in hypertensive older adults: The NEET Trial; • Improve PAD PERformance with METformin: The PERMET Trial; • ENabling Reduction of low-Grade Inflammation in Seniors with losartan and omega-3 polyunsaturated fatty acids: The ENERGISE Trial; • Nicotinamide riboside and walking exercise intervention to reduce fatigue in older breast cancer survivors: Exercise and Nutritional Ergogenic to ReGain Energy: The ENERGE Study; and • NICotinamidE riboside with and without resveratrol to improve functioning in peripheral artery disease: The NICE Trial.

The most recent and largest clinical trial just funded by the NIH and initiated is Cocoa flavanols to improve walking performance in PAD: the COCOA-PAD III Trial. In the pilot study (completed R21) we showed a positive result in walking speed using cocoa (main active ingredient: epicatechin) and was published in Circulation Research. In that study we showed a therapeutic effect of cocoa on walking performance in people with PAD. This warranted the larger Phase III clinical trial to definitively determine whether cocoa significantly improves walking performance in people with PAD. (a) McDermott MM et al. Cocoa to Improve Walking Performance in Older People with Peripheral Artery Disease: The COCOA-PAD Pilot Randomized Clinical Trial. Circ Res. 2020; (b) Pahor M et al. Effect of Losartan and Fish Oil on Plasma IL-6 and Mobility in Older Persons. The ENRGISE Pilot Randomized Clinical Trial; J Gerontol A Biol Sci Med Sci. 2019. (c) McDermott MM et al. Effect of Low-Intensity vs. High-Intensity Home-Based Walking Exercise on Walk Distance in Patients with Peripheral Artery Disease: The LITE Randomized Clinical Trial. JAMA. 2021; and (d) McDermott MM et al. Effect of Resveratrol on Walking Performance in Older People with Peripheral Artery Disease: The RESTORE Randomized Clinical Trial. JAMA Cardiol. 2017.

B. Summary. My laboratory (since 1998 at UF; Biochemistry of Aging Laboratory) has been very productive translating basic and preclinical findings into clinical trials. I also work closely with the NIH Intervention Testing Program (ITP). The ITP is designed to test nutritional-pharmacological interventions to extend lifespan. Previously, we have been involved in intervention testing (i.e., rapamycin, aspirin, nordihydroguaiaretic acid, and glycine), and our recent ITP proposal C2021 on epicatechins (flavanol) was selected to start in 2022. I am very active in various Center grants. I am one of the principal investigators for the AHA’s Vascular Diseases SFRN. This project’s overall goal is to identify specific Mt defects associated with skeletal muscle pathophysiologic changes in elderly patients with vascular disease. The focus of another Center grant (a P50 and now an RM1) is to better understand the causes and consequences of sepsis in elderly surgery or trauma ICU patients. I am nationally and internationally recognized for my research and scholarship and also have multiple active national and international collaborations outside of UF.

I am working on the mechanism underlying aging with the C. elegans model, which can provide more knowledge for the aging of human beings.

The Someya Lab studies the molecular mechanisms that underlie cochlear mitochondrial dysfunction, aging, and hearing loss. Our work employs molecular genetics tools to identify the genes and pathways involved in aging and mitochondrial dysfunction. These studies are complemented by the use of electrophysiology and histology to assess hearing function and cochlear pathology. We use mice as a model system because the mouse inner ear is anatomically similar to that of human and the homologies between the mouse and human genomes are well-established.

http://someyalab.aging.ufl.edu/about-someya-lab/