Sci. Aging Knowl. Environ., 8 March 2006
Vol. 2006, Issue 6, p. nf8
[DOI: 10.1126/sageke.2006.6.nf8]


Buffing Up the Family Jewels

Obliterating a protein that fosters testosterone production keeps testicles young

Mary Beckman

Coaches can hurt their athletes by working them out too long or too hard. Similarly, a protein that keeps testicles making sperm wears down the organ, new research shows. The results suggest a new tactic to prevent testicle damage.

Elderly men produce as little as one-third the amount of testosterone as hormone-addled 20-year-olds do. This so-called andropause can bring on osteoporosis, loss of muscle mass, and diminished libido. Previous research on older animals has shown that the Leydig cells in the testes slow manufacture of testosterone. However, researchers can dampen output of the hormone in adolescent rats by infusing them with testosterone; large quantities of the hormone in the blood quash Leydig cell function. If they let testosterone production resume when the animals are old, the cells make youthful quantities of the hormone. The Leydig cells' apparent ability to pick up where they left off suggests that the cells don't age simply in response to cues from the external environment. Instead, they can behave as if they are young even when they reside in an old body. Something in the testes seems to promote Leydig cell aging, presumably a substance connected to testosterone production. In cultured cells from old testes, a normal testicular protein called PACAP stimulates worn-out Leydig cells to crank up testosterone production. So Lacombe and colleagues tested whether PACAP influences testosterone yield and testicular aging in animals.

First, the team engineered mice to lack PACAP. Both young and old altered animals made unusually small amounts of testosterone. At 4 months of age, the testes of normal animals and those lacking PACAP looked similar. But 11 months later, when the mice were in their dotage, the organs of normal mice had degenerated, whereas those of PACAP-lacking mice were still robust. Holes riddled normal animals' tissue, and many sperm-making cells had died off. This observation suggested that PACAP damages the testes.

The researchers then investigated whether PACAP controls testosterone manufacture in the gonads or tinkers with hormones in the brain's pituitary gland that regulate testosterone production. Quantities of two such pituitary hormones were similar in normal and engineered rodents. However, amounts of two testicular proteins needed to make testosterone had plunged in PACAP-deficient mice. The researchers restored production of these proteins by injecting 4-month-old altered animals with PACAP. Together, the results imply that PACAP frazzles the testes directly, perhaps by promoting manufacture of testosterone. Aside from low sperm counts, the PACAP-missing mice appear to be healthy; they scurry around, eat their normal quantities of food, and show no signs of illness.

The work suggests that "the more active a cell is in generating steroids, the more likely it will damage itself over time," says reproductive biologist Matthew Hardy of Rockefeller University in New York City. Although loss of PACAP appears to maintain the health of the testes, the researchers need to perform further experiments to confirm that conclusion, he says: They should restore PACAP in the altered animals for long enough to show that its presence will run down the testes. "The actions of PACAP that promote reproductive fitness early in life are apparently associated with costs in terms of early aging [of the testes]," says endocrinologist Andrzej Bartke of Southern Illinois University School of Medicine in Springfield. Hardy says the work suggests new therapies for andropause. Current strategies replace testosterone and ignore Leydig cells. "Perhaps we can change Leydig cell function" by fiddling with proteins such as PACAP that regulate the testosterone factories, he says. Training the cells to work a little slower might help lengthen their active season.

March 8, 2006
  1. A. Lacombe et al., Delayed testicular aging in pituitary adenylate cyclase-activating peptide (PACAP) null mice. Proc. Natl. Acad. Sci. U.S.A. 103, 3793-3798 (2006). doi 10.1073/pnas.0505827103 [Abstract/Free Full Text]
Citation: M. Beckman, Buffing Up the Family Jewels. Sci. Aging Knowl. Environ. 2006 (6), nf8 (2006).

Science of Aging Knowledge Environment. ISSN 1539-6150