Do we have any idea why most geroprotective drugs seem to work better in one sex than in the other?
While we don’t know why several of these drugs either work only in males or work better in males, there are several clues. Let me tell you about three of them.
One has to do with improvements in function like balance and grip, strength, and endurance on a rotating rod. Michael Garrett has studied several of these in mice treated with either 17α-estradiol, which is male-specific for lifespan, or acarbose, which males respond to better.
He finds that most of the performance measures are improved by acarbose and 17α-estradiol only in male mice. But there are a few that are improved even in female mice. In this way, you can begin to sort out what aspects of improved health are seen in both sexes and what aspects are seen only in males and presumably contribute to their lifespan benefit.
Similarly, people in my lab like Gonzalo Garcia have evaluated biochemical indices. Gonzalo has looked at enzymatic cascades in particular. He’s looked at two sets of kinases, one of which is really important in inflammation and the other in terms of protein translation.
When you look at the cascade that is important in inflammation, all the drugs, rapamycin, acarbose, or 17α-estradiol, cause benefits in that particular set of cascades in both males and females. So that’s not likely to be a key element of the lifespan control pathway because 17α-estradiol does not improve lifespan in females, it’s males only, and yet it does improve this kinase cascade.
The other kinase cascade, the one that focuses on protein translation, does show sexual specificity for 17α-estradiol in Gonzalo’s assays. Only the males benefit from 17α-estradiol. So, this is a hint that of the many cellular changes that these drugs produced, some, like the ones that lead to protein translation, at least show the same pattern of behavior as lifespan and may be important to lifespan. Others, like the inflammatory kinase cascade, respond to all the drugs, and that means that they’re probably not involved in the lifespan effect, which is male-specific for this. The more drugs we have that can be thrown into this analysis, the more likely it is that we’ll zero in on the specific pathways by which these drugs produce health benefits and lifespan improvements.
Our current search is to look for biochemical and physiological changes that are produced by all those drugs, as well as by four single-gene mutations that extend lifespan, and by caloric restriction. So, we have eight such changes so far – things that you can measure in young adult mice after drug treatment, or in the four mutants, or after calorie restriction. And they all change in the same way.
Most, though not quite all of them, are sex-specific for the 17α-estradiol treatment. We think that these physiological changes are our best glimpse as to what aspects of biology have to be changed, at least in mice, to get a lifespan increment.
This is also a link to human biology because you can ask, okay, I’m giving this drug to humans. Do any of these changes happen? If the answer is yes, that’s a sign that the drug may be very important in terms of controlling the human aging processes or at least links to the human biology and human diseases.
