NIH/NIA – Geroscience Approaches to Alzheimer’s Disease (R01, R21 Clinical Trial Not Allowed)

March 12, 2019 by School of Medicine Webmaster

The following description was taken from the R01 version of this FOA.

The basic biology of aging affects the functional performance of all organs in the body, including the brain. The field of geroscience aims to understand, at the cellular and molecular level, the interconnections between aging and disease/disabilities, with a focus on understanding the mechanisms by which aging contributes as the major risk factor for most chronic diseases. The geroscience hypothesis posits that manipulation of aging will simultaneously delay the appearance or severity of multiple chronic diseases because these diseases share the same underlying major risk factor: the aging process.

Recent progress in the field of aging biology has allowed researchers to develop robust behavioral, genetic and pharmacological approaches to expand the lifespan of multiple species. Importantly, interventions that extend lifespan often result in improvements in multiple aspects of healthspan, resulting in significant delays in the appearance of pathology and frailty. Conversely, when lifespan is shortened, diseases and frailty occur earlier. In other words, disease susceptibility scales with the lifespan of the organism.

As for other chronic diseases of the elderly, Alzheimer’s disease (AD) is not an exception in that aging is the major risk factor for sporadic AD, and as mentioned, this risk is the centerpiece of the geroscience hypothesis. Importantly, modifying the rate of aging has already been shown to modify resilience to pathological challenges, including in genetic mouse models of AD. Understanding the role of the basic biology of aging thus provides new venues for research and inquiry into the etiology of this disease. A better understanding of the role of aging biology in the advent of AD might also lead to badly needed new therapeutic approaches.

AD is a progressive, multifactorial disease with multiple symptoms, the best-recognized of which is neurodegeneration. In addition to plaques and tangles formed in the brain, many AD patients have symptoms in other tissues, but the relationship of these symptoms to the dementia itself is unknown, suggesting that the disease is systemic, and as such, it might be susceptible to interventions that act systemically. Indeed, there is substantial evidence in the literature indicating that Alzheimer’s patients develop multiple diseases and functional decline in peripheral systems, often before the onset of overt neurologic disease.

This initiative aims to test whether interventions known to systemically affect the rate of aging are effective as modulators of the incidence, progression, etiology and treatment of AD. The goal of this initiative is to fund several independent teams that will perform research to advance our understanding of the role of aging in the development and etiology of AD, using approaches that manipulate the rate of aging via behavioral, genetic, or pharmacological interventions, and using animal models developed for AD. Researchers are encouraged to use commonly used AD models that display neuronal AD phenotypes, such as triple transgenic, Tg2576, 5x FAD mice, and others. In addition, non-rodent models of AD, including invertebrates, are also welcome. NIA also strongly encourages the use of new models being developed by the MODEL-AD consortium. In other words, the goal is to test whether appearance of AD symptoms, both in the brain and the periphery, scale with lifespan in animal models of AD. Such a scaling of lifespan and healthspan has been shown to occur in other disease models and across a large portion of the phylogenetic scale. Specifically, researchers have identified a handful of hallmarks of aging, and tools exist to either accelerate or decelerate these deteriorative processes in multiple species, including behavioral approaches such as caloric restriction, time-restricted and CR-mimicking diets, as well as genetic (reduction in IGF-1 or mTOR, or activation of sirtuins, for example) and more recently, multiple pharmacological approaches, including those identified by the NIA Interventions Testing Program (rapamycin, 17alpha estradiol, acarbose) and others such as senolytics or NAD+ enhancing drugs. These interventions have been shown to lead to an apparent slowing of the aging process, accompanied by a delayed appearance of multiple diseases and improved resilience. Applications will be expected to include, at a minimum, expertise in basic aging biology, geroscience, animal models and AD.

Areas of interest include, but are not limited to:

  • Crossing animal models of accelerated or decelerated aging to currently used animal models of AD.
  • Manipulation of the rate of aging by pharmacological means, in animal models of AD.
  • Examination of the mechanistic role played by pillars of aging in the development, progression and etiology of AD. These include cell senescence, systemic inflammation, proteostasis and others, as described in the literature.

Deadline:  June 2, 2019 (letters of intent); July 2, 2019 (full proposals)


Filed Under: Funding Opportunities