Associate Professor of Internal Medicine and Adjunct Assistant Professor of Nutrition and Integrative Physiology
Aging, Obesity, Adipose, Artery, Atherosclerosis, Inflammation, Metabolism
The age of the US population is steadily increasing as is the prevalence of overweight and obesity, and both aging and obesity are primary risk factors for cardiovascular and metabolic diseases. My laboratory’s broad research interest is to understand the mechanisms underlying vascular and metabolic dysfunction and disease with advancing age as well as to understand how this is exacerbated by overweight/obesity.
Ongoing Research Projects:
Effects of Aging and Obesity on the Adipose Tissue and its Vasculature:
While once thought of as a merely a storage site for energy, the adipose tissue is now recognized as an endocrine organ that plays a central role in metabolic dysfunction in obesity. The adipose also demonstrates dysfunction with advancing age and may contribute to both vascular and metabolic disease by dysregulating lipid handling and contributing to systemic inflammation.
My laboratory is interested in elucidating both the role that adipose tissue dysfunction may play in age-associated vascular and metabolic dysfunction and the mechanisms by which aging and obesity lead to dysfunction in the adipose tissue and its associated vasculature. In particular, we are exploring the role of telomere dysfunction and cellular senescence and dysregulated signaling through the small GTPase, ARF6, in these processes.
Effects of Aging on Arterial Function and Atherosclerosis:
Advancing age is associated with vascular dysfunction and increased risk of cardiovascular diseases such as atherosclerosis, although the underlying mechanisms are incompletely understood. My laboratory seeks to elucidate the role of mTOR, miR-92a and ARF6 in age associated arterial dysfunction and atherosclerosis.
Inhibition of mTOR with rapamycin has been demonstrated to increase lifespan in mice, suggesting that mTOR activation with aging may play a central role in the aging process. My laboratory seeks to elucidate the role of altered mTOR signaling in the vascular aging phenotype and to explore the use of novel interventions that can mimic the beneficial effects of rapamycin.
MicroRNAs (miRs) are small noncoding RNAs that regulate translation of messenger RNA and have important physiological effects, acting on multiple gene targets often related to a specific cellular process/signaling pathway. MiR-92a, a member of the miR-17-92 cluster, is important in vascular growth during development and tumorogenesis and is decreased in advanced age. Our laboratory seeks to determine if an age-associated reduction in microRNA, miR-92a and its cluster miR-17-92, underlies age-associated arterial dysfunction and accelerated atherosclerosis.
Age-associated chronic inflammation is implicated in both arterial dysfunction and atherosclerosis. Activation of the small GTPase, ADP ribosylation factor 6 (ARF6), is associated with inflammatory states, but the impact of aging on arterial ARF6 is not known. Because ARF6 is also known to be sensitive to changes in shear stress, we seek to determine if ARF6 signaling modulates endothelial function, inflammation and mechanotransduction of turbulent / oscillatory shear and contributes to the development of age-related pro-atherosclerotic arterial dysfunction.
References (Selected Publications)
- Trott DW, Machin DR, Phuong TT, Adeyemo AO, Bloom SI, Bramwell RC, Sorensen ES, Lesniewski LA, Donato AJ (2021). T cells mediate cell non-autonomous arterial aging in mice.(Epub ahead of print) J Physiol.
- Trott DW, Islam MT, Buckley DJ, Donato AJ, Dutson T, Sorensen ES, Cai J, Gogulamudi VR, Phuong TTT, Lesniewski LA (2021). T lymphocyte depletion ameliorates age-related metabolic impairments in mice. Geroscience, 43(3), 1331-1347.
- Islam MT, Holland WL, Lesniewski LA (2021). Multicolor fluorescence biosensors reveal a burning need for diversity in the single-cell metabolic landscape.(Epub ahead of print) Trends Endocrinol Metab.
- Islam MT, Hall SA, Lesniewski LA (2021). Chronic aerobic exercise: targeting two birds with one stone. J Physiol, 599(4), 1015-1016.
- Islam MT, Henson GD, Machin DR, Bramwell RC, Donato AJ, Lesniewski LA (2020). Aging differentially impacts vasodilation and angiogenesis in arteries from the white and brown adipose tissues. Exp Gerontol, 142, 111126.
- Machin DR, Auduong Y, Gogulamudi VR, Liu Y, Islam MT, Lesniewski LA, Donato AJ (2020). Lifelong SIRT-1 overexpression attenuates large artery stiffening with advancing age. Aging, 12 (12), 11314-11324.
- Zhang Y, Ecelbarger CM, Lesniewski LA, Müller CE, Kishore BK (2020). P2Y2 Receptor Promotes High-Fat Diet-Induced Obesity. Front Endocrinol (Lausanne), 11, 341.
- Phuong TTT, Walker AE, Henson GD, Machin DR, Li DY, Donato AJ, Lesniewski LA (2019). Deletion of Robo4 prevents high-fat diet-induced adipose artery and systemic metabolic dysfunction. 26(5), e12540.
- Walker AE, Breevoort SR, Durrant JR, Liu Y, Machin DR, Dobson PS, Nielson EI, Meza AJ, Islam MT, Donato AJ, Lesniewski LA (2019). The pro-atherogenic response to disturbed blood flow is increased by a western diet, but not by old age. Sci Rep, 9(1), 2925.
- Lesniewski LA, Seals DR, Walker AE, Henson GD, Blimline MW, Trott DW, Bosshardt GC, LaRocca TJ, Lawson BR, Zigler MC, Donato AJ (2017). Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways. Aging Cell, 16(1), 17-26.
- Donato AJ, Henson GD, Hart CR, Layec G, Trinity JD, Bramwell RC, Enz RA, Morgan RG, Reihl KD, Hazra S, Walker AE, Richardson RS, Lesniewski LA (2014). The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: evidence of significant multisystem dysfunction. J Physiol, 592(18), 4083-96.
- Lesniewski LA, Hosch SE, Neels JG, de Luca C, Pashmforoush M, Lumeng CN, Chiang SH, Scadeng M, Saltiel AR, Olefsky JM (2007). Bone marrow-specific Cap gene deletion protects against high-fat diet-induced insulin resistance. Nat Med, 13(4), 455-62.