The Undoing Aging conference, a collaboration between the SENS Research Foundation and Michael Greve’s Forever Healthy Foundation, took place on March 15-17 in Berlin, which saw many researchers, advocates, investors, and other important members of the longevity community gather together to learn about the latest progress in rejuvenation biotechnology.
LEAF arranged a travel grant for Anna Dobryukha, one of the best Russian journalists writing about aging, longevity, and rejuvenation research, to join us, so it made sense to collaborate with her on the most interesting interviews. Anna works for Komsomolskaya Pravda, one of the largest Russian publishing houses, which has a newspaper, a radio station, and a website with over 40 million readers.
Today, we have an interview that Anna did with professor Brian Kennedy during the conference. Professor Kennedy is an important figure in the aging research field, and he studies multiple mechanisms known to influence lifespan, such as sirtuins and the TOR pathway.
TOR created considerable interest when it was shown recently that the drug rapamycin, a compound that inhibits TOR, can reliably extend mouse lifespan. One of the goals of his research is to determine whether pathways like TOR can be manipulated to treat age-related diseases.
The interview included Anna Dobryukha and Brian Kennedy, plus Elena Milova, and Steve Hill from LEAF.
Elena: So, my first question is who is aging faster, do different aspects of aging become visible for men or women?
Brian: Well, it’s been known for a long time that women live longer than men, and the question has always been, is that because men are more likely to die of things unrelated to aging, or is it because women just age more slowly? Most people feel that women age slightly more slowly, but the interesting thing is that if you look at the demographics over the last 20 or 30 years, the increase in lifespan is happening more in men than women, so it suggests that men are catching up to women in most countries. That may also suggest that the lifestyle factors in men have, in the past, been accelerating aging, and now that’s being reduced.
Elena: At what age do men normally start to get aging, and what age do women start to get aging, approximately?
Brian: I think that depends on how you define aging. The processes that are causing aging are going on, in my opinion, throughout life; it’s just that your body adapts to damage and things that happen throughout most of your life, and, at some point, you can’t adapt anymore, and when you can’t adapt, that’s when you start getting sick and you get one disease or another. Those chronic diseases are starting in our 50s and 60s, and I’m not sure if anyone’s looked carefully at the onset of those diseases in men and women, at least in terms of whether there’s a consistent trend; it’s certainly true that women are more susceptible to some diseases and men others, but I’m not sure if it’s been shown that women have a general delay in the onset of chronic disease. That question’s hard to answer; it depends on what you mean by “when does aging start?” I think that there are a lot of processes that are happening throughout adulthood; it’s just that we don’t notice them until enough bad things happen that our bodies can’t compensate.
Elena: What can you say about the difference of how women and men age? What is the difference, and how much is it?
Brian: I think that, first of all, one of the striking features is that if we look at animal models, the drugs and genetic mutations that extend lifespan, almost all of them work better in one sex than the other; sometimes, it’s females better than males, sometimes, it’s males better than females, and I think that’s telling us that there are intrinsic differences in how men and women age. One of the things that seems to be true, although it’s early stage, is that anti-inflammatory factors tend to work better in males, and so that suggests to me that the levels of chronic inflammation that happen during aging may be more of a factor in men than women. That’s the kind of information that we are starting to learn from these studies, but it’s still early days. I would also say that the hormonal influences on aging are probably big drivers in the differences of how men and women age. We’re testing that now using a variety of mouse genetic models, but it’s still preliminary. Women undergo a rapid loss of estrogen with menopause. In fact, in old age, men tend to have higher estrogen levels than women, whereas with testosterone, there’s a gradual decline, and that’s led a lot of people to speculate as to whether replacing these hormones is good for aging or not. It’s not clear. It’s possible that the loss of testosterone is more of a compensatory factor and that it’s protective. Most of the studies that supplement testosterone don’t suggest that it makes men live longer, so there’s a lot to be done still with trying to understand estrogen and testosterone, and it’s highly debated in literature, especially when it comes to things like estrogen replacement therapy. If you want to start an argument, ask people whether estrogen replacement therapy’s a good idea or not, and you can sit back and have your coffee while everybody argues.
Anna: Can you please give us some examples of drugs or supplements that are known to affect men and women differently?
Brian: Well, one of the drugs, rapamycin, has a bigger effect in females than males, for lifespan in animals. We don’t have much human data on these drugs for aging yet. We’re still going based on animal data, but things like aspirin and 17-alpha-estradiol [Alfatradiol], and acarbose, which is a diabetes drug, extend lifespan in male animals and not females, in mice.
Anna: So, for males, they’re better?
Brian: Yes, they work better for males, and we really don’t know why. That was a surprising observation, especially with acarbose, which blocks carbohydrate uptake in the gut. There’s still big questions to be answered in that area. But we need to know, because as we start doing clinical trials in humans looking at aging, it’s going to be really important to try to identify the subgroups that are going to respond the best so that we get significant results. Being able to predict whether something is going to work in males or females is highly beneficial in that context.
Anna: Could you please name the main factors why men live shorter lives than women?
Brian: Certainly, one factor is that there’s a blip in mortality in men right around the teenage years into early adulthood that doesn’t tend to exist in women. That’s one contributing factor; we call that testosterone poisoning, jokingly. There are also certain chronic diseases that men are more likely to get earlier; more women suffer from heart disease with aging, but men tend to get it earlier than women do, so it’s more of a later-age disease in women. There’s a differential onset of a number of different diseases, and there are environmental factors too, like smoking, especially in Russia, alcohol consumption, which is much higher in men. Alcohol consumption is actually probably protective at low levels, but at high levels, it’s very toxic.
Anna: There was an article recently about the effects of pregnancy on life expectancy. Apparently, it was said that pregnancy can make women age faster. What do you think about it?
Brian: I think it still remains controversial. There have been studies on both sides; there’ve been studies that say that women who have multiple pregnancies are likely to live longer. I haven’t seen that recent study, but I think that’s a very controversial area of research still. It’s unclear whether pregnancy is protective or actually detrimental for aging, at least in my mind.
Anna: How does sexual behavior affect life expectancy in men and women; is there a difference or not?
Brian: I haven’t seen strong data on that. My sense is that maintaining sexual activity is probably healthy, provided it’s done in a safe way, probably in both sexes. But I can’t cite hard data supporting that; I think that’s a general perception, and I’m not sure how much is hopeful thinking. Unsafe sex practice is certainly a risk factor.
Elena: Can we say that an anti-aging treatment that reverses aging completely is going to be different for men and women?
Brian: I think that what we’ll find is that whenever we test interventions, we’ll find a lot of them that’ll have different effects in men and women. In general, I think it is going to be possible to extend lifespan and healthspan in both men and women, but I think we’ll find that some interventions, just like in the animal models, work better in men and others work better in women.
Anna: We’ve met with you a few times already, and we’ve seen many things develop in the rejuvenation industry. What are the main breakthroughs so far, and what can we expect in the future?
Brian: I think there’ve been two major breakthroughs in the last five to ten years. The first is that instead of one or two potential interventions, now we have dozens of potential interventions that may work for aging, and I don’t know which ones are going to translate to humans yet, but we have so many shots on goal now that I think some of these shots are going to go in, so that excites me. The other thing is that we now have a number of candidate biomarkers of aging. I’m not sure if any of them are completely validated yet, but a number of them look quite strong. That is really critical as we go into human testing. We have to have something to measure, and we have good candidate markers to measure now. The next step is to really test these interventions in humans, and that’s one of the things that I’m looking to do in Singapore, but I think other people are as well. We’ve learned a lot, and we have to start understanding how these things affect humans, or we’re going to reach a bottleneck.
Anna: What fields of research do you find the most promising so far?
Brian: I think there’s a whole range of different translational approaches to aging. Some are testable now, like drugs, and others are still being developed, like gene therapy and plasma replacement, that sort of thing. I’m not sure, in the long run, which is going to be the most prominent. My main goal is to show that some of the early things work, even if they have small effects, because I think once people begin to realize that we can change aging and extend healthspan, then there will be plenty of resources to do the more fancy things down the road.
Steve: We all know that you work on metabolism; what are your thoughts in regards to people like myself practicing calorie restriction in an effort to improve health and hit longevity escape velocity?
Brian: I think that calorie restriction is likely to affect aging in humans. I don’t know if it’ll get you all the way to escape velocity, but I think it’s likely to work. The problem is, I don’t recommend it generally because I think that it’s very difficult to effectively do calorie restriction, and if you’re going to cut your calories way down, you still have to get the right balance of macronutrients and all the micronutrients you need. Most people that aren’t educated probably don’t do that effectively, and they end up being malnourished. That is why I like to encourage intermittent fasting approaches and other fasting strategies because I think they’re safer, and they’re likely to give you some of the benefits of calorie restriction at the same time.
Steve: So, something along the lines of Valter Longo’s strategy.
Brian: I am a member of his board, so full disclosure, but El Nutro is one of the ways to do it. There’s also the 5-2 diet and time-restricted eating, and I think all of them show promise. I can’t really even tell you which ones are going to work better than others at this point.
Steve: Well, everybody’s different as well, so they react to diets differently, so it is difficult, isn’t it?
Brian: Not only do people react to diets differently, but it’s affected by exercise. One of the debates right now is whether you need a low-protein diet or a high-protein diet. I think that’s going to be highly influenced by how much you exercise during the day as well, and we’re still not doing enough studies where we compare multiple lifestyle factors against each other in a matrix. I think that might underscore some of the differences we see in optimal diets for people.
Steve: Exercise is certainly a good strategy for aging because there was a study last week released by Birmingham University that showed that thymic shrinking was greatly reduced for cyclists who were very active for most of their lives. They seemed to think it was interleukin-7 that promoted growth and offset the shrinkage. I think exercise is probably one of the best things that you can do for anti-aging right now right?
Brian: No arguments there; I agree.
Anna: What do you feel are the main bottlenecks that are slowing down research on aging and the development of anti-aging treatments right now?
Brian: I think that it’s resources and also effective strategies that do clinical trials. Like I said before, we’ve learned a lot from animal models; don’t get me wrong; there’s a lot to be done on animal models, and I think they still need to be funded. But we certainly know enough now that we’re ready to start testing things in humans, and there’s just not enough of that going on right now.
Anna: Do you have any ideas to share on the best way to solve this? What can our community do, what can academia do, and what should regulatory agencies be doing in order to have translational medicine?
Brian: I don’t know that anybody has the right answers. We are looking, in Singapore, to try to do short- to intermediate-term studies trying to cross-compare the effects of a list of interventions against a list of potential biomarkers so that we can begin to link these specific interventions to biomarkers. But it’s a bit of a guessing game; we don’t know if three to six months of intervention is sufficient to have big changes on the epigenome or not. We don’t know what it’s going to do to other factors that are measuring aging as well. It’s a little bit of a guessing game right now. The other way to do it is to do what Nir Barzilai’s doing and do very long-term trials looking at prevention of multiple diseases, but that costs a fortune, and it’s hard; we’d like to test ten different interventions, not just one. I’m not sure which of us has the right answer or if any of us do at this point, but if you don’t get in there and start trying, you’re not going to figure it out. Ultimately, we’ll figure out the best way to do it.
Steve: I’m involved with mice, which are easier to control from a genetic point of view; they don’t vary that much, but humans can vary a great deal.
Brian: I would agree with that, but I also think that the variation we see with the aging of Black 6 mice is striking given that they have an identical genotype going in. So, you’re right, I think we are going to find personalized issues with human aging. The more we learn how to predict who’s going to respond to what intervention, the better chance we have of showing efficacy. Right now, it’s pilot studies, but hopefully, we’ll get enough knowledge from those that we’ll be able to design the right ones in the next generation.
Steve: That’s the problem with humans, you see; they’re under an ad libitum diet regime. People eat different diets; they exercise or don’t exercise, they have different lifestyles; how do you factor that in with studies? I suppose the only choice, really, is larger cohorts to compensate for it.
Brian: Larger means more expensive, too.
Steve: Yeah, that’s the problem, but I can’t see any way of avoiding it.
Brian: Ultimately, it may be the case. If we can just start getting pilot data, we can at least do power calculations based on the pilot data and then know what size we need to look at.
Anna: Thank you very much.
We would like to thank Anna for collaborating with LEAF at the conference and Professor Kennedy for taking the time to do this interview.
