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As individuals reach middle age, it’s common for them to notice an increase in waist size, a change that goes beyond mere aesthetics. The accumulation of abdominal fat is known to expedite the aging process and hinder metabolic functions, potentially heightening the risk of conditions such as diabetes and heart disease. Research into the mechanisms of this shift has been limited, until now.
Recent preclinical studies conducted by City of Hope®, a prominent cancer research and treatment institution in the U.S. that also specializes in diabetes and other serious health issues, have shed light on the cellular mechanisms responsible for age-related abdominal fat. This research, published in the journal Science, points to a promising target for future therapeutic interventions aimed at curbing belly fat and enhancing longevity.
“It’s common for individuals to experience a loss of muscle mass and an increase in body fat in their later years, even if their overall body weight remains constant,” stated Qiong (Annabel) Wang, Ph.D., the co-corresponding author of the study and an associate professor at the Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope. “Our research has revealed that aging promotes the emergence of a unique type of adult stem cell, which significantly boosts the production of new fat cells, particularly in the abdominal region.”
Collaborating with Xia Yang, Ph.D., from UCLA, Wang and her team conducted experiments on mice, which were subsequently validated with human cell studies. Their investigation concentrated on white adipose tissue (WAT), the fat responsible for weight gain as a result of aging.
While it is established that fat cells enlarge as an individual ages, the researchers suspected that WAT also produces new fat cells, suggesting an extensive potential for growth within this tissue.
To validate their hypothesis, the scientists honed in on adipocyte progenitor cells (APCs), which are stem cells found in WAT that develop into fat cells.
The team transplanted APCs from both young and older mice into a separate group of younger mice. The results showed that APCs from older mice rapidly produced a significant number of fat cells.
In contrast, when young APCs were transplanted into older mice, there was minimal production of new fat cells. This outcome demonstrated that aging APCs have a robust capacity for generating fat cells, independent of the age of their host.
Through single-cell RNA sequencing, the researchers examined the gene activity of APCs in both young and older mice. They found that while APCs in younger mice were largely inactive, those in middle-aged subjects were highly active, resulting in a surge of new fat cell production.
“In most adult stem cells, the ability to proliferate diminishes with age; however, APCs behave differently—aging seems to activate their potential to grow and multiply,” noted Adolfo Garcia-Ocana, Ph.D., who chairs the Department of Molecular & Cellular Endocrinology at City of Hope. “This research provides the first evidence that the increase in belly fat as we age can be attributed to the prolific nature of APCs in generating new fat cells.”
Additionally, aging transformed APCs into a new category of stem cells known as committed preadipocytes, or CP-As. Emerging during middle age, these cells are instrumental in generating new fat cells, which helps explain the weight gain observed in older mice.
A critical signaling pathway, the leukemia inhibitory factor receptor (LIFR), was found to play a vital role in this process, promoting the proliferation and conversion of CP-A cells into fat cells.
“Our findings revealed that the fat production process requires LIFR signaling in older mice, which is not the case for younger mice,” Wang explained. “This signal appears essential in orchestrating CP-As to produce new fat cells and contribute to increased abdominal fat in older individuals.”
Following this, the team investigated human tissue samples of various ages, identifying similar CP-A cells with a pronounced ability to create new fat cells in middle-aged individuals.
“These insights underline the importance of managing the formation of new fat cells as a strategy for tackling age-associated obesity,” Wang emphasized. “By understanding the role of CP-As in metabolic issues and their development during aging, we could pave the way for new medical strategies aimed at reducing abdominal fat and enhancing health outcomes.”
Future research efforts will aim to track the behavior of CP-A cells in animal models, observe their characteristics in humans, and develop innovative methods to inhibit or eliminate these cells to help mitigate age-related fat accumulation.
The study’s lead authors include Guan Wang, Ph.D., from City of Hope, and Gaoyan Li, Ph.D., from UCLA.
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