Source: TEXAS A&M UNIVERSITY submitted to
IMPROVING THE HEALTH SPAN OF AGING ADULTS THROUGH DIET AND PHYSICAL ACTIVITY.
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
COMPLETE
Funding Source
HATCH
Reporting Frequency
Annual
Accession No.
1022678
Grant No.
(N/A)
Cumulative Award Amt.
(N/A)
Proposal No.
(N/A)
Multistate No.
NE-1939
Project Start Date
Apr 7, 2020
Project End Date
Sep 30, 2024
Grant Year
(N/A)
Program Code
[(N/A)]- (N/A)
Project Director
Sun, YU.
Recipient Organization
TEXAS A&M UNIVERSITY
750 AGRONOMY RD STE 2701
COLLEGE STATION,TX 77843-0001
Performing Department
Nutrition & Food Science
Non Technical Summary
Aging is often accompanied by obesity, and obesity promotes chronic inflammation. Chronic inflammation is prevalent in aging, which is linked to a wide range of age-related diseases such as diabetes, cardiovascular disease, and cancer. A major mediator of inflammation is a type of immune cells, called macrophages. Aging tissues have increased pro-inflammatory macrophages, which releases harmful factors to the circulation and into the tissue environment causing tissue damage.Ghrelin is a gut hormone which functions through growth hormone secretagogue receptor (GHS-R). GHS-R is present in macrophages, and its levels in macrophages increase under obesity and aging. We reported that deletion of GHS-R protects against age-associated obesity and inflammation. We hypothesize that GHS-R is important in control of macrophage function during aging, and GHS-R inhibition mitigates age-associated inflammation, improving overall health. To study the function of GHS-R in macrophages, we generated a unique mouse model with GHS-R deleted selectively in macrophages. We will subject these mice to regular diet or high-fat diet (HFD) to mimic normal aging and aging obesity, respectively. We anticipate that GHS-R is a crucial factor in macrophage reprogramming during aging, affecting lifespan and healthspan. The "proof-of-concept" studies in this proposal will provide critical evidence as to whether GHS-R blockade represents a unique strategy for combating aging and age-related diseases.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
30339991010100%
Knowledge Area
303 - Genetic Improvement of Animals;

Subject Of Investigation
3999 - Animal research, general;

Field Of Science
1010 - Nutrition and metabolism;
Goals / Objectives
To conduct multidimensional assessments of diet, physical activity and related factors affecting aging adults.
Project Methods
We hypothesize that GHS-R is important in control of macrophage function during aging, and GHS-R inhibition mitigates age-associated inflammation, improving overall health. We will use our newly generatedGhsr-MφKO mice to unravel the roles and pertinent mechanisms of GHS-R in macrophage reprogramming in aging, and its associated lifespan and healthspan. We will subject these mice to regular diet or high-fat diet (HFD) to mimic normal aging and aging obesity, respectively. Age-related immune impairment is characterized by stem cell exhaustion, telomere shortening, and disruption of cell-to-cell communication. To determine the roles and underpinning mechanisms of GHS-R in aging immunity and aging-associated phenotypic outcomes, we will carry out the following Specific Investigations:Aim 1. Determine the roles of myeloid GHS-R in lifespan and healthspan. Study Ghsr-MφKO mice under normal aging (feeding regular diet) and aging obesity (feeding HFD) to determineAim 2. Determine the effects of myeloid GHS-R on microphage infiltration and polarization in adipose tissue, liver, muscle, pancreas, colon and brain. Aim 3. Interrogate the cellular/molecular mechanisms associated with GHS-R mediated macrophage polarization by unbiased and targeted approaches.

Progress 04/07/20 to 09/30/20

Outputs
Target Audience:Scientists, trainees, aging public, elderly with chronic diseases. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?In last year, I have trained 7 undergradue and 5 granduate stundets in the lab. How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals? "Aim 1. Determine the roles of myeloid GHS-R in lifespan and healthspan. Study Ghsr-MφKO mice under normal aging (feeding regular diet) and aging obesity (feeding HFD) to determine: 1A) Lifespan: Survival rate by assessing length of survival. 1B) Healthspan: frailty score, cognitive functions, circulating inflammatory cytokine levels and C-creative protein, fecal and plasma metabolites (to assess gut leakiness), glucose tolerance and insulin sensitivity will be evaluated every 6 months throughout lifespan. Aim 2. Determine the effects of myeloid GHS-R on microphage infiltration and polarization in adipose tissue, liver, muscle, pancreas, colon and brain. Young (4-months), middle-aged (12-months) and old (20-months) Ghsr-MφKO and control mice will be subjected to the following studies: 2A) Polarization analysis of peritoneal and tissue macrophages, as well as Bone Marrow Derived Macrophages (BMDM), by flow cytometry. 2B) Metabolic profile by Seahorse extracellular flux to assess M1-promoting anabolic glycolysis and M2-promoting catabolic fatty acid oxidation; 2C) Morphological characterization of tissues by immunofluorescence to detect macrophage quantity and inflammation master regulator NF-kB. 2D) Investigate the effect of aging immunity on genetic aging by assessing telomerase activity in BMDM of old mice." Based d on the aims above, next reporting period, we will continue carryover lifespan and healthspan studies in Aim 1. We are planning to catch up on flow cytometry experiments in BMDM and Seahorse analysis in Aim 2. In addition, since scientific community now emphasizes that biological studies need to conduct in both male and female. Our data so far are mostly in male mice. Another major focus next period is to build up female mouse colony and conduce key experiments. We aim to submit 3 manuscripts for publication: 1. The role of macrophage GHS-R deficiency in liver steatosis; 2. The role of macrophage GHS-R in high fat diet-induced meta-inflammation.

Impacts
What was accomplished under these goals? Low-grade chronic inflammation is a hallmark of aging which affects a wide range of tissues; this phenomenon is termed "inflamm-aging". Aging correlates with increased obesity, which is known to induce low-grade chronic inflammation in tissues such as adipose tissue and liver. Growth hormone secretagogue receptor (GHS-R) is the recognized receptor for nutrient-sensing gut hormone ghrelin. We found that GHS-R has a pivotal role inflammation in adipose tissue and liver of aging mice, GHS-R activates metabolic pathways to reprogram macrophage polarization toward a pro-inflammatory M1 state, subsequently eliciting meta-inflammation in adipose tissues and liver. We have had 4 publicaitons in 2020 related to aging.

Publications

  • Type: Conference Papers and Presentations Status: Published Year Published: 2020 Citation: 1. Chia-Shan Wu, Qiong Wei, Hongying Wang, Da Mi Kim, Miriam Balderas, Guoyao Wu, John Lawler, Stephen Safe, Shaodong Guo, Sridevi Devaraj, Zheng Chen, Yuxiang Sun (2020). Protective effects of ghrelin on fasting-induced muscle atrophy in aging mice. Journal of Gerontology 75:621-630. 2. Hong-ying Wang, Min Wu, Jun-ling Diao, Ji-bin Li, Yu-xiang Sun and Xiao-qiu Xiao (2020). Huperzine A ameliorates obesity-related cognitive performance impairments involving neuronal insulin signaling pathway in mice. Acta Parmacological Sinica 44:145-153. 3. Min Wu, Maolin Liao, Rongfeng Huang, Chunxiu Chen, Tian Tian, Hongying Wang,Jiayu Li, Jibin Li, Yuxiang Sun, Chaodong Wu, Qifu Li, Xiaoqiu Xiao (2020). Hippocampal overexpression of TREM2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia. Genes & Diseases (in press). 4. Yuxiang Sun (2020). A Cautionary Note for COVID-19 Survivors: Potential Long-term Risk for Alzheimers Disease. American Journal of Biomedical Science & Research (AJBSR), 001415.