The Undoing Aging conference, a collaboration between the SENS Research Foundation and Michael Greveβs 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, itβs 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 thatβs 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; itβs just that your body adapts to damage and things that happen throughout most of your life, and, at some point, you canβt adapt anymore, and when you canβt adapt, thatβs when you start getting sick and you get one disease or another. Those chronic diseases are starting in our 50s and 60s, and Iβm not sure if anyoneβs looked carefully at the onset of those diseases in men and women, at least in terms of whether thereβs a consistent trend; itβs certainly true that women are more susceptible to some diseases and men others, but Iβm not sure if itβs been shown that women have a general delay in the onset of chronic disease. That questionβs hard to answer; it depends on what you mean by βwhen does aging start?β I think that there are a lot of processes that are happening throughout adulthood; itβs just that we donβt notice them until enough bad things happen that our bodies canβt 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, itβs females better than males, sometimes, itβs males better than females, and I think thatβs telling us that there are intrinsic differences in how men and women age. One of the things that seems to be true, although itβs 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. Thatβs the kind of information that we are starting to learn from these studies, but itβs 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. Weβre testing that now using a variety of mouse genetic models, but itβs 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, thereβs a gradual decline, and thatβs led a lot of people to speculate as to whether replacing these hormones is good for aging or not. Itβs not clear. Itβs possible that the loss of testosterone is more of a compensatory factor and that itβs protective. Most of the studies that supplement testosterone donβt suggest that it makes men live longer, so thereβs a lot to be done still with trying to understand estrogen and testosterone, and itβs 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 therapyβs 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 donβt have much human data on these drugs for aging yet. Weβre 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, theyβre better?
Brian: Yes, they work better for males, and we really donβt know why. That was a surprising observation, especially with acarbose, which blocks carbohydrate uptake in the gut. Thereβs 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, itβs 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 thereβs a blip in mortality in men right around the teenage years into early adulthood that doesnβt tend to exist in women. Thatβs 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 itβs more of a later-age disease in women. Thereβs 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, itβs 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; thereβve been studies that say that women who have multiple pregnancies are likely to live longer. I havenβt seen that recent study, but I think thatβs a very controversial area of research still. Itβs 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 havenβt seen strong data on that. My sense is that maintaining sexual activity is probably healthy, provided itβs done in a safe way, probably in both sexes. But I canβt cite hard data supporting that; I think thatβs a general perception, and Iβm 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 weβll find is that whenever we test interventions, weβll find a lot of them thatβll 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 weβll find that some interventions, just like in the animal models, work better in men and others work better in women.
Anna: Weβve met with you a few times already, and weβve 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 thereβve 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 donβt 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. Iβm 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 thatβs one of the things that Iβm looking to do in Singapore, but I think other people are as well. Weβve learned a lot, and we have to start understanding how these things affect humans, or weβre going to reach a bottleneck.
Anna: What fields of research do you find the most promising so far?
Brian: I think thereβs 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. Iβm 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 donβt know if itβll get you all the way to escape velocity, but I think itβs likely to work. The problem is, I donβt recommend it generally because I think that itβs very difficult to effectively do calorie restriction, and if youβre 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 arenβt educated probably donβt 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 theyβre safer, and theyβre likely to give you some of the benefits of calorie restriction at the same time.
Steve: So, something along the lines of Valter Longoβs strategy.
Brian: I am a member of his board, so full disclosure, but El Nutro is one of the ways to do it. Thereβs also the 5-2 diet and time-restricted eating, and I think all of them show promise. I canβt really even tell you which ones are going to work better than others at this point.
Steve: Well, everybodyβs different as well, so they react to diets differently, so it is difficult, isnβt it?
Brian: Not only do people react to diets differently, but itβs affected by exercise. One of the debates right now is whether you need a low-protein diet or a high-protein diet. I think thatβs going to be highly influenced by how much you exercise during the day as well, and weβre 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 itβs resources and also effective strategies that do clinical trials. Like I said before, weβve learned a lot from animal models; donβt get me wrong; thereβs a lot to be done on animal models, and I think they still need to be funded. But we certainly know enough now that weβre ready to start testing things in humans, and thereβs 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 donβt 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 itβs a bit of a guessing game; we donβt know if three to six months of intervention is sufficient to have big changes on the epigenome or not. We donβt know what itβs going to do to other factors that are measuring aging as well. Itβs a little bit of a guessing game right now. The other way to do it is to do what Nir Barzilaiβs doing and do very long-term trials looking at prevention of multiple diseases, but that costs a fortune, and itβs hard; weβd like to test ten different interventions, not just one. Iβm not sure which of us has the right answer or if any of us do at this point, but if you donβt get in there and start trying, youβre not going to figure it out. Ultimately, weβll figure out the best way to do it.
Steve: Iβm involved with mice, which are easier to control from a genetic point of view; they donβt 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, youβre right, I think we are going to find personalized issues with human aging. The more we learn how to predict whoβs going to respond to what intervention, the better chance we have of showing efficacy. Right now, itβs pilot studies, but hopefully, weβll get enough knowledge from those that weβll be able to design the right ones in the next generation.
Steve: Thatβs the problem with humans, you see; theyβre under an ad libitum diet regime. People eat different diets; they exercise or donβt 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, thatβs the problem, but I canβt 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.
