Exploring the consequences of differential… (F32AG090007) – Project Grant to Vanderbilt University

Abstract: Worldwide, the number of adults over the age of 60 will double to 2.1 billion by 2050, leading to an enormous rise of age-related, non-communicable diseases (ncds) such as dementia, type 2 diabetes, and cardiovascular diseases. Previous work with small-scale, subsistence-level groups suggests that these "diseases of aging" may be avoidable and not an inevitable part of getting older. For example, age-matched samples of tsimane forager-horticulturalists in bolivia exhibit the lowest levels of coronary artery disease in the world and slower brain atrophy than americans and europeans. The ability of subsistence-level groups to "escape" age-related diseases has been hypothesized to be partially driven by differential immune investment across the life course: these groups are highly physically active, often resource constrained, and constantly exposed to immune threats-all factors which are predicted to keep the runaway sterile inflammation associated with many ncds in check. However, no study to date has used modern 'omics tools to understand age effects on immune investment in subsistence-level contexts, or how lifestyle change may directly alter these patterns. The central objective of this study is to use a multi-omic approach to understand the effect of lifestyle on immune activity across aging. Using within and between-population comparisons, i will test how immunological aging varies between individuals experiencing diverse lifestyles, ranging from traditional subsistence-level to highly urban lifestyles. To do so, i will work with the tsimane of bolivia, the turkana of kenya, the orang asli of malaysia, and with public data generated from US individuals. I will focus on three molecular phenotypes from peripheral blood that are known to be age-associated in post-industrial contexts-gene expression, DNA methylation (dnam), and clonal hematopoiesis of indeterminate potential (chip)-and i will characterize these features in subsistence-level tsimane, turkana, and orang asli. I will then explicitly ask how lifestyle variation impacts patterns of aging and immune function using (i) cross-population comparisons between these subsistence-level groups and a highly urbanized population (i.e., the US) and (II) within-population comparisons, as subsets of the turkana and orang asli have recently moved to urban city centers while others still practice their traditional pastoralist (turkana) or hunter-gatherer (orang asli) lifestyles. I predict that the energy excess characteristic of sedentary, calorie dense urban lifestyles will be associated with age-related changes in somatic mutation rates as well as inflammatory dnam and gene expression, while in subsistence-level settings immune variation will primarily track pathogen responses with blunted age effects. Importantly, i will assess these predictions using both within- and between-population comparisons to reveal robust, generalizable results. Together, this study will illuminate how urbanization impacts immunological aging typical of ncds and will generate extensive 'omics and health knowledge for historically marginalized groups that are chronically under-represented in genomic studies.

Action	Obligated	Date
Amendment	$81,151	Jul 30, 2025
Amendment	$79,459	Jul 22, 2024
Amendment	$0	Jul 22, 2024
Original award	$79,459	Jul 22, 2024

Exploring the consequences of differential immune investment on molecular aging phenotypes in subsistence-level populations

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