Colder and Wiser: The impacts of aging on thermoregulation

Art Courtesy of Breanna Brownson.

Babies don’t shiver when they’re cold—at least for the first six months of their lives. Instead, they keep warm through a mechanism called non-shivering thermogenesis, in which a special type of fat called brown adipose tissue generates heat. But as babies grow older, thermogenesis is no longer their primary means of keeping warm. According to a study by researchers at multiple centers, including Yale, age-related changes in thermoregulatory control arise from changes in the body’s immune system. The authors discovered that aging impairs a specific kind of immune cell called type 2 innate lymphoid cells (ILC2s), which are important for the maintenance of healthy adipose (fat) tissue.

We have two types of fat in our bodies: white adipose tissue (WAT) and brown adipose tissue (BAT). Aging is marked by a decline in brown adipose tissue and a shift in the distribution of white adipose tissue. As we grow older, we have an increase in white adipose tissue in our trunk and abdomen. This visceral adipose tissue is subject to enhanced inflammation and insulin resistance, which increases the risk of obesity among the elderly.

There also exists a third type of body fat midway between white and brown adipose tissue: beige adipose tissue, which arises from white fat parent cells but possesses similar features to brown fat cells. Beige adipose tissue also responds to cold exposure via energy expenditure and heat production. 

The scientists looked into ILC2s because of their role in visceral adipose tissue “browning,” the production of beige fat cells. They compared the immune compartment differences between young and old mice models and found that there was an almost complete loss of ILC2s in the visceral adipose tissue of older mice.

ILC2s are tissue-specific immune cells, meaning they stay within the visceral adipose tissue after their generation in the bone marrow. ILC2 development depends on the proliferation of IL-33, which belongs to a class of small cell-signaling proteins that regulate our immune systems. The research team found that IL-33 was produced in different cellular locations in the adipose tissue of young versus old mice. This switch in cellular source led them to believe that there is less IL-33 available to develop ILC2s. Less ILC2s means less browning, and thus a weakened cold tolerance. 

The authors hypothesized that if they could supplement IL-33 in old mice, the resulting ILC2 development would restore healthy cold response. They examined this through the “cold challenge” method, during which mice were placed alone in cages that were kept at around forty degrees Fahrenheit. Experimenters checked on the mice twice a day to monitor mortality rates, then took adipose tissue samples from mice that survived for two straight days to look for signs of a healthy cold response.

So, can IL-33 alone fix the immune system of older mice? In short, it can’t. Actually, mice with supplemented IL-33 had a higher mortality rate than did other old mice in the cold challenge. Their response to cold and temperature regulation was still entirely dysfunctional.

Faced with totally unanticipated results, the researchers came to realize that maybe the problem wasn’t with IL-33 at all: it was with the ILC2s themselves. Using RNA sequencing, they discovered that ILC2s of old mice are pathogenic. Simultaneously, there are very few healthy ILC2s left to offset these negative effects. While the researchers were unable to determine the exact mechanism of old ILC2 lethality, it certainly seems to be a double-edged sword that leads to the dysfunction of the thermogenic response.

The research team tried one last experiment. ILC2s from young, healthy mice were directly transplanted into older mice. Only then did the thermogenic response increase and mortality rates in the cold challenge decrease. 

These results caution us that attempting to “fix” an immune pathway can be tricky—we don’t know if we could be causing more problems than we solve. “With age, the immune system has already changed, and we need to be careful how we manipulate it to restore the health of the elderly,” said principle investigator Vishwa Deep Dixit, Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology at Yale, in an interview with YaleNews. 

Fully understanding how to repair the immune system could be a game changer for the elderly or people with immune deficiencies. “Immune cells play a role beyond just pathogen defense and help maintain normal metabolic functions of life,” Dixit told YaleNews. These other functions include cold response and regulation of fat. Armed with more knowledge of why the immune system stops working, researchers like Dixit can continue to work towards solutions that will lead to a healthier population in more ways than one.