A quarter of aged mice died within two days of being moved into a cold room, while mice made obese by a high-fat diet all survived a week in the same chill. A new study in the journal Nature points to a surprising culprit. A chain of signals linking nerves, immune cells, and stress hormones helps keep brown fat, the body’s built-in heater, turned down as animals age.
Researchers blocked one link in that chain, a docking site for stress hormones called the glucocorticoid receptor, using a drug called RU-486. After a week of treatment, aged mice had more heat-burning fat cells and used more energy, even though they ate and moved no more than untreated mice. Survival after treatment was not reported, so the results speak only to heat output.
Anyone who has watched a grandparent reach for a sweater on a warm afternoon will find the puzzle familiar. Brown fat burns calories to make warmth, and its output falls with age, which the authors link to cold sensitivity. In these experiments, that decline behaved like an active brake.
Brown Fat Cells Split Into High-Heat and Low-Heat Types
Researchers at City of Hope in California worked mostly with mice, plus fat tissue from five people having thyroid surgery (four women and one man, ages 18 to 48). Some brown fat cells burn fuel hard to make warmth, while others idle.
Tracking which was which, the team found an enzyme called H6PD that piled up in idling cells and stayed scarce in heat-burning ones. Human tissue near the collarbone showed a similar either-or pattern.
H6PD helps switch on a stress hormone inside the cell, and that hormone then tells the cell to stop building its main heat-making protein. When researchers removed H6PD from lab-grown fat cells, the gene for that protein became sixfold more active. H6PD acts as a dimmer on heat production.
Immune Cells Hold Brown Fat in Low-Heat Mode
Two kinds of immune cells, neutrophils and macrophages, keep H6PD from breaking down by releasing an inflammation signal called IL-1β. Fat cells sitting near clusters of that signal tended to idle, while cells farther away tended to burn heat.
In mice moved into the cold, nerves lowered the inflammation signal, H6PD broke down, and more fat cells switched to heat-burning. When researchers cut the nerves leading to the fat, that switch was blunted. Nerves tell immune cells, and immune cells tell fat cells, like a relay.
A second experiment tested what shuts the heaters off once the cold ends. Mice engineered to lose the glucocorticoid receptor in their heat-burning cells after a week of cold stayed in heat-burning mode through another week back at room temperature. They also used more energy and oxygen, with no change in body weight. The authors propose that flipping between the two states lets the body respond quickly to cold, and may spare fat cells from the strain of burning at full blast.
Cold Intolerance in Aged Mice Is Linked to Excess IL-1β
To test aging, the team compared male mice at 10 weeks old with male mice at 75 weeks old, all placed in a 43-degree-Fahrenheit room. Survival was tracked in 37 young and 38 aged mice. Aged mice ran colder than young ones, while the obese mice, which were also young, held up fine. Brown fat in the obese mice held less H6PD and more heat-making protein than in mice on regular chow, a sign the heating system stayed intact. Aging and obesity seem to dampen heat production through different routes.
Aged brown fat carried about six times as much activity from the gene that makes the inflammation signal as younger tissue did. At room temperature, only 0.3 percent of its cells were in heat-burning mode, compared with nearly 29 percent in young mice. Even after three days in the cold, about half of the aged cells had switched on, against roughly 90 percent in young ones. Earlier studies have found that aged brown fat attracts more immune cells, which fits that picture.
Blocking One Receptor Partly Restored Heat Output in Old Mice
Aged mice, 70 to 75 weeks old, received daily RU-486 injections for a week. Heat-burning cells rose from under 1 percent to about 8 percent at room temperature, and from about 11 percent to about 33 percent after a day in the cold. Treated mice also ran warmer in a cold test, and their brown fat cells held less stored fat.
In energy-tracking cages, seven comparison mice and eight treated mice were monitored for a full day and night. Treated mice used more energy and oxygen, with no change in food intake or activity. Most cells still idled after treatment, so the repair was partial.
Cold sensitivity in older age may come down to a signaling problem with a specific target, one that could someday be treated. RU-486 acts across the whole body, though, so other organs may have contributed, and any benefit in people remains untested. A drug aimed at brown fat alone is the logical next experiment.
