How Aging Stem Cells Contribute to Midlife Weight Gain

The increase in waistlines during middle age is a common occurrence, but its implications extend beyond mere appearance. An accumulation of abdominal fat can accelerate aging and impair metabolic functions, thereby heightening the risk of chronic illnesses such as diabetes and cardiovascular diseases. However, the mechanisms that drive this transformation from toned physiques to softer abdomens have remained largely unclear.

Recent research conducted by City of Hope has identified a cellular mechanism responsible for age-related abdominal fat accumulation, offering new perspectives on managing midlife weight gain. The findings, published in the journal Science, indicate potential therapeutic targets to mitigate the effects of age on body composition.

As aging progresses, individuals often experience a loss of muscle mass along with an increase in body fat, even if their overall weight remains stable. The research team, led by experts at City of Hope, discovered that aging prompts the emergence of a new category of adult stem cells, which significantly boosts the production of fat cells, particularly in the abdominal region.

The collaboration with a UCLA laboratory involved experiments on mice, which were later corroborated with human cell studies. The researchers focused on white adipose tissue (WAT), which is primarily responsible for weight gain associated with aging. While it is widely recognized that fat cells increase in size as a person ages, the study posits that WAT also expands through the generation of new fat cells, suggesting a potentially limitless capacity for growth.

To investigate this phenomenon, the researchers examined adipocyte progenitor cells (APCs), a specific type of stem cell within the WAT that differentiates into fat cells. They conducted experiments wherein APCs from both younger and older mice were transplanted into a cohort of younger mice. The results indicated that APCs from older mice rapidly produced a significant number of new fat cells, whereas those from younger mice did not demonstrate similar activity when placed in older hosts.

Further analysis using single-cell RNA sequencing revealed a stark contrast in gene activity between APCs in young and middle-aged mice. In young mice, APCs exhibited minimal activity, but those in middle-aged counterparts became highly activated, leading to an increased generation of fat cells.

While most adult stem cells typically lose their growth potential with advancing age, the opposite appears to be true for APCs, which gain a heightened capacity for proliferation as individuals age. This study marks a significant finding, highlighting that the expansion of abdominal fat in older age is due to the prolific activity of these APCs.

Additionally, aging transforms APCs into a novel type of stem cell known as committed preadipocytes (CP-As), which significantly contribute to fat cell production. The study identified a crucial signaling pathway, the leukemia inhibitory factor receptor (LIFR), as essential for the proliferation of CP-As into mature fat cells.

The researchers discovered that while young mice can produce fat without the activation of LIFR, older mice rely on this signaling mechanism to facilitate fat production. This indicates that LIFR plays a pivotal role in stimulating CP-As, leading to increased abdominal fat accumulation in aging mice.

To further validate their findings, the team analyzed human adipose tissue samples across different age groups. Results demonstrated the presence of similar CP-A cells in humans, with a notable increase in their numbers in middle-aged individuals, underscoring their significant role in fat cell formation.

The implications of this research are considerable, as they underscore the importance of regulating the formation of new fat cells to combat obesity linked to aging. Understanding the behavior and emergence of CP-As in metabolic disorders may pave the way for innovative medical strategies aimed at reducing abdominal fat and enhancing overall health as individuals age.

Future investigations will focus on tracking CP-A cells in animal models and observing their activity in humans, aiming to develop interventions that could inhibit or block these cells to prevent age-associated weight gain.