Lab focus

My research has focused on various aspects of aging: (i) the effects of aging and dietary restriction on gene expression in rats and mice and the mechanism responsible for genotype differences in response to dietary restriction, (ii) testing the oxidative stress theory of aging by measuring the effect of alterations in the antioxidant defense system on the lifespan and pathology of transgenic and knockout mice, and (iii) studying the effect of rapamycin on aging and age-related diseases. My laboratory is currently studying the role of chronic inflammation in aging and developing a novel rat model to study aging and test anti-aging interventions.
Cellular senescence and necroptosis are two cell-fate pathways that have been proposed to play a role in the age-related increase in chronic inflammation, or ‘inflammaging’. Cellular senescence was discovered in the 1960s and is now recognized as one of the primary mechanisms of aging. Senescent cells accumulate in a variety of tissues with advancing age and reducing senescent cell burden through genetic or pharmacological approaches increases lifespan and improves many physiological functions that decline with age. Senescent cells produce and secrete biologically active compounds, termed the senescent-associated secretory phenotype (SASP). The ‘bystander’ effects of SASP-factors on neighboring cells are believed to lead to changes associated with the loss of function and pathology that occurs with aging, especially inflammaging.
In contrast to senescence, necroptosis has been studied only in the past 15 years. Necroptosis is the programmed lysis of cells resulting in the generation of damage-associated molecular patterns (DAMPs), which are potent inducers of inflammation. Because of its role in inflammation, our group studied the role of necroptosis in inflammaging. We found that necroptosis increased with age, was reduced by dietary restriction and in long-lived Ames dwarf mice, and increased in Sod1-/- mice, a model of accelerated aging and frailty. We also found that the increase in necroptosis was paralleled by an increase in inflammation, suggesting that necroptosis was important in inflammaging. To directly test this possibility, we used pharmacological and genetic approaches to inhibit necroptosis and found that suppressing necroptosis dramatically reduced inflammation. When we measured markers of senescence, we were surprised to find the following: (1) pharmacological inhibition of necroptosis reduced senescence in old and Sod1-/- mice and (2) genetic inhibition of necroptosis reduced senescence in old mice. In addition, we found that (3) pharmacological elimination of senescent cells reduced necroptosis in Sod1-/- mice; (4) genetic elimination of p16+ cells reduced necroptosis; and (5) inhibition of necroptosis improved the phagocytotic activity of liver macrophages. Based on these preliminary data, we hypothesize that an interaction occurs between necroptosis and senescence resulting in a vicious feedback cycle that leads to the deleterious consequences of these two cell-fates on aging, such as inflammaging. We propose that SASP-factors produced by senescent cells induce adjacent cells to undergo necroptosis, resulting in the release of DAMPs. The DAMPs bind to cell surface receptors on innate immune cells inducing an inflammatory response and the production of proinflammatory cytokines. We propose that DAMPs also increase the burden of senescent cells in a tissue either by paracrine/juxtacrine signaling and/or by reducing the clearance of senescent cells by macrophages. The result is a positive feedback-loop where the secretion of SASP-factors increases necroptosis and the release of DAMPs, which in turn induce more senescent cells - creating a vicious cycle that results in inflammaging and the pathology/diseases associated with aging. We are testing this hypothesis using conditional knockout and novel knockin mouse models we have developed to block or induce necroptosis in specific cells/tissues.

Why it matters

Chronic, low-grade inflammation that occurs with age (inflammaging) has been observed in all mammalian species studied [e.g., rodents, rhesus monkeys, and humans and has been identified as one of the ‘seven pillars of aging’. Because inflammation is strongly associated with a variety of diseases (e.g. type 2 diabetes, cardiovascular disease, cancer, neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, and frailty), it has been argued that inflammaging is an important factor in the etiology of these diseases. In addition, disease and environmental conditions that reduce lifespan and increase various age-related diseases (e.g. obesity, HIV-infection, and exposure to cigarette smoke) are also associated with increased inflammation. On the other hand, studies with mice show that interventions that increase lifespan, e.g., dietary restriction, dwarfism, and rapamycin treatment reduce inflammation. These data have led to the view that inflammation plays an important role in the mechanism underlying aging and age-related diseases. However, almost all the data in support of role of inflammation in aging are correlative. Using knockout and knockin mouse models we will be able to directly test the impact of blocking or inducing necroptosis on inflammation and aging.