Location: Jean Mayer Human Nutrition Research Center On Aging
Project Number: 8050-10700-004-003-R
Project Type: Reimbursable Cooperative Agreement
Start Date: Oct 1, 2022
End Date: May 31, 2025
Objective:
ARS has found that the normal gut bacteria, Parabacteriodes distasonis (Pd) blocks inflammation and strengthens gut barrier function in mice. The gut barrier is comprised of a mucus layer as well as a layer of epithelial cells bound tightly together by tight junctions and adherins junctions. The gut barrier limits the penetration of bacterial antigens into the intestinal tissue and blood stream. These antigens can cause colonic and systemic inflammation and compromise function (psychomotor and cognitive), longevity, and cancer risk. A key component of the tight junctions is the protein ZO-1. ARS found Pd to robustly increase ZO-1 expression in mice and 3 cell lines. Most importantly, we recently found that Pd significantly increases lifespan and activity in 2 strains of fruit fly. In fruit fly longevity has been closely linked to gut barrier.
Objectives:
1) To determine if Pd can increase lifespan in mice;
2) To determine in Pd increases healthspan in mice, to be measured via a battery of
psychomotor and cognitive tests;
3) To determine if ZO-1 depletion decreases lifespan and health span in mice; and
4) To identify the Pd factor that up-regulates ZO-1.
Approach:
1) To determine if Pd can increase lifespan in mice: A survival study will be conducted in which mice are fed diets supplemented with 0 or 0.04% Pd. Median and maximal survival will be compared between groups;
2) To determine if Pd increases healthspan in mice: In mice from Aim 1 we will perform a battery of tests to assess various aspects of frailty including:
--motor function, co-ordination and strength = rotarod, grip strength, plank/rod walk-
-memory= morris or barnes maze, novel object recognition
--inflammaging= blood cytokines and LPS
Measures will be conducted at 200, 400, 600, 800 and 1000 days of age.
3) To determine if ZO-1 depletion decreases lifespan and health span in mice: Survival
curves will be compared between wildtype and ZO-1 (intestinal) knockout mice. The measures of frailty described above (in #2) will be conducted; and
4) To identify the Pd factor that up-regulates ZO-1: Multiple common bacteria will be screened for their ability to upregulate ZO-1.
