Thank you everyone for attending a fun discussion on the science of healthy aging. It was great to receive such poignant questions and I'll do my best to address them all. Please don’t hesitate to get in touch with me or visit the Buck at Buckinstitute.org to see how you can learn more about aging research and our members program!
From the top, a brief disclaimer. Everything I write in answer does not constitute medical advice and you should consult with your physician before making and lifestyle changes.
Fasting – the whats the hows and the whys
I received several questions on fasting so I’m going to try and answer them in one go here.
Let me just clarify what fasting entails first. Fasting is abstaining from all foods and drinks with caloric value. So allowed things include tea and coffee without creamers and of course plenty of water. There also exists a fasting mimicking diet, or FMD, if you want something easier but apparently as effective as water only fasting. It was devised by professor Voltar Longo at USC and his research has shown that the FMD is very effective at reducing mTOR activity and promoting immune system regeneration. Essentially, it's a 5 day very low calorie, ketogenic diet - that is, it promotes the body switching to using primarily fats for fuel in the form of ketone bodies.
Someone asked a great question: 24hr once a week vs daily for 14 hr, which is better. The truth is no one has directly tested this and certainly not robustly in humans. I don't think anyone has ever assessed the benefits of fasting 1 day per week on longevity, even in mice. For daily intermittent fasting, the evidence seems to suggest the longer the non-eating window the better. Mouse and human studies increasing the fasting window from 12 to 14 to 16 to 18 hours all shows benefits on markers of metabolic health and the all-important circadian clock. In some ways it's a biochemistry question i.e., how long does it take for your cells to turn on autophagy to clear away those damaged components and turn on the stress response genes that protect cells from harmful reactive oxidants? Several studies have shown that prolonged fasting (24,48hrs+) leads to a robust increase in autophagy. It's less clear how much autophagy increases over a 14 hr daily fast. I think the key is finding something you can stick with. I struggle to extend my daily fast beyond 14 hours, but I try and make up for that by partaking in a longer fast (36-72hrs) every so often.
An interesting study in mice, found that eating two meals a day with a long fasting window in between i.e., eat from 8-10am then don't eat again til 5-7 pm can also lead to increased autophagy and improvements in metabolic markers. It's worth pointing out that, in that eating schedule, the total daily fast is about 20hrs, just split up into one 8hr fast and one 12 hour fast. From a practical perspective, a 14hr daily fast is a lot more achievable for most people. However, the data supports the notion that the longer you fast, the better for clearing away harmful protein aggregates.
I want to also highlight the power of eating in a short window to support something called Circadian Entrainment. We are all familiar with the idea of our circadian rhythm which dictates how our body functions in cycles over a 24-hour, light-dark period. The genes that regulate our metabolism, wakefulness, satiety, immune system (just about everything actually!) change over a 24-hour period. The data in animal and human studies suggest that the more pronounced and defined the cycle of gene expression is over a 24-hour period, the better coordinated our organs and cells become. A young adult has a very pronounced rhythm, whereas older adults lose this, and the cycle becomes ‘flatter’. Studies suggest that one way to improve the circadian entrainment of our genes is to restrict our eating window. From an evolutionary perspective, it makes sense that food is a signal to our circadian clock because of how we evolved. Our ancestors, on the plains of Africa, would have only found/caught food during the daylight hours and probably only during defined, cooler periods of the day such as dawn and dusk. We should never eat when it's dark. The closer we are to our naturally evolved rhythm, the healthier our bodies behave. This also applies when thinking about exercise. Hunter gatherers likely walked for at least 6 miles per day and every evidence suggests modern hunter gatherers do not suffer from age-related diseases even into their 60s, 70s and 80s.
Personally, I practice one 36 hr fast every 2-3 weeks and then a prolonged 3-5 day fast every 4-6 months. I am 29 years old and in good health but the prolonged fast can be very tough. I have done both forms of fasting and I think the FMD is easier on the body but in some ways harder your psychology during the fast. I also advocate not just for restricting food but for improving the quality of the food we consume. Limiting carbohydrates and refined sugars is an important part of limiting the insulin signaling pathway I described as the master regulator of aging.
Exercise – what types are good?
This has been one of my burning questions for over a decade. Thankfully the research has some of the answers and I'm doubly thankful that it turns out to be quite simple. Every type of exercise is good! With that said, I'll break this down into three bodily systems to consider.
1: The cardiovascular system. The health of the CV system is critical to protect us from CV diseases such as atherosclerosis and heart disease, as well as maintaining our lung function so we can continue to do the things we love without getting out of breath or lightheaded. There is ample evidence to suggest that low intensity aerobic exercise is extremely protective for the CV system as we age. So, what is low intensity anyway? The simplest way to measure it is by perceived effort. Think, the kind of effort where it just becomes uncomfortable to hold a conversation going. I tend to think of walking uphill, or moderate speed on the elliptical or biking. If you have a heart rate monitor or smart phone with the heart rate monitor app you could also use the following formula: 180 beats per minute - your age. So, if you're 65, that's 115bpm. Working at this bpm for 30-40 minutes a few times a week is probably the single best thing you can do for your CV system as you age. Recent evidence suggests that we risk over working the CV system if we push it more than that level on a very regular basis. Higher intensity work such as the increasingly popular High Intensity Interval Training or HIIT should probably play a role in staying functional over our lifetime because there will be times when we need to work hard for a short burst, such as running for a flight if we're late, and we want to be able to rev the engine, so the speak. But I would limit that to only one session per week or fortnight. I would advise against exercise that puts a lot of shock through the joints since joints fail to heal properly once damaged - it's just a quirk of our biology that we can't regenerate them very well.
2: The musculoskeletal system. The musculoskeletal system declines in strength and robustness with aging. The good news is exercise can, for the most part, slow down this process. If you want strong bones and muscles, you must stress them a little. That means resistance training such as lifting weights or using resistance bands, but it could also mean simply practicing getting up and down from the floor which is a critical skill for remaining independent into our 80s and 90s. I recommend a regular yoga practice with a focus on foundational poses such as the warrior sequences which strengthens the core, glutes and legs. Again, I would strongly advise against high impact sports that could stress the joints.
3: The brain and mind. It has been known for a long time that regular exercise causes improvements in working memory and general performance on cognitive tests, but the question is what drives this process. Interestingly, this seems to work because exercise reduces inflammation in the body. Inflammatory signals tend to build up in our body due to aging and exercise ameliorates that. I chose to include the mind here because it can't be understated how much exercise can improve mental health. Moreover, a huge study out of Scandinavia looking at which types of exercise were most protective in terms of lifespan and healthspan showed that activities which involved socializing, for example, soccer and tennis, had the biggest impact. This was only an observational study, but my takeaway is that the best exercise is exercise that is fun, social and will keep you coming back.
What about someone in their 80s with multiple chronic diseases including heart failure and arthritis? Can they still slow down their aging?
This is a very tricky question to answer. I think the key for older individuals who don’t already exercise is to start off slowly and take it easy. I would caution that anything should be monitored by a PCP or personal trainer so as to not cause problems with the heart. Diet is a very powerful tool to improve overall health and I would advise to simply improve the quality of the diet. The Mediterranean diet high in heart healthy fats such as olive oil and fatty fish is very protective against cardiovascular disease. There was a multi-year, clinical trial looking at the effectiveness of 1 tbsp of olive oil per day for preventing cardiac events and it was so effective they ended the trial early because it would have been unethical to not give the intervention to the placebo arm of the trial. Reducing sugar in the diet is also a huge step in the right direction. From my talk you might remember I went to lengths to show how the main aging processes are driven by Insulin. Insulin is directly controlled by blood sugar and by extension the sugar in our diet. Therefore, limiting carbohydrates and sugar is a very good strategy for improving your metabolic health even in old age. Cruciferous veggies also contain chemicals that stimulate the bodies defense systems to make us age slower.
So how do we know if the things we do are actually working?
This is a fantastic question and something I’ve thought about for myself. How can we tell if an intervention is working? Certainly, we can check our lipid panel to see if we’ve decreased our risk of cardiovascular disease and some physicians now measure a protein call LP(little a) which is a true measure of risk for atherosclerosis. You might also consider other metabolic markers such as fasting glucose but that’s maybe less informative than we might think because it’s just a snapshot in time. Now, there are some very interesting recent breakthroughs for measuring your biological age. I’ll share two options, the first you will be able to get tested through your PCP, the second would be an out-of-pocket expense but is more informative about your underlying aging rate.
For the first, head over to the website called http://aging.ai/ They have made a free tool where you can input the results of blood tests and it will compute your biological age. If you click on one of the three aging.ai options and then ask your PCP to order tests that will cover all those markers. Of course, this depends on your financial situation and your insurance coverage so please be aware of that before proceeding.
For the second, you may or may not have heard of the “methylation clock”. This is a very exciting aging discovery in the past 5 years. Basically, they find that the DNA in our cells seems to collect these marks on it over time in a very reliable pattern. In fact, it’s so reliable that we can build a biological clock based on it. Some people have a pattern of marks on the DNA that is younger than their chronological age and others show the opposite. It turns out that it can even predict the age you will be when you die – kind of scary! The good news is that it is actually a malleable thing - interventions we know slow the rate of aging such as caloric restriction and exercise also seem to slow the biological aging clock as measured by these methylation marks. These are now available to consumers and you can simply order a saliva test and mail it back to them for between $150 and $250 dollars. You could take a test to get a baseline and then in a few years take it again to see if you’ve aged slower.
Anti-aging, senolytic supplements – Fisetin
I received an interesting question about the supplement Fisetin for anti-aging which I think is worth a brief discussion:
Fisetin is an interesting molecule. It is a plant derived flavonoid, like many bioactive molecules we consume in our regular diet such as apigenin found in chamomile tea and quercetin found in apples and other fruits or vegetables. Fisetin is touted as an anti-aging compound because it appears to kill senescent or zombie cells. It is important to point out that while the experiments using senolytics on mice appear to be remarkable in terms of health and aging, senescent cells are not always a bad thing. One critically important role of senescent cells is in wound healing. Senescent cells recruit the immune system to a wound or damaged part of the body to allow the body to heal efficiently. They showed this in mice by deliberately wounding the skin and then either killing or not killing the senescent cells at the site of the injury. They found the mice where the cells were killed healed far slower and were more likely to get scarring. Moreover, not all damaged cells will become zombie cells and in fact there may be a period in which these damaged cells can recover and return to normal. We really don’t want to kill other cells which might not be replaced, especially in an older person in whom stem cells may not replenish tissue so well. The problem with the Fisetin studies is that they have failed to demonstrate if Fisetin also kills non-senescent, damaged cells. I think Fisetin is an interesting compound with potentially very exciting antioxidant and anti-senescence properties but I’m reluctant to take it as an anti-aging supplement without further research in humans – human research is key.
So, what about Rapamycin? Can we take it?
Rapamycin is a controlled substance because it is actually quite dangerous in moderate to high doses because at those doses it inhibits the immune system. If you want to consider being prescribed Rapamycin off-label, at low doses or on an intermittent regimen then there are some doctors who are appraised of the science enough to prescribe it for aging. One such doctor is Alan Green, MD but he is based in NY and I believe only takes in-person consultations. While I don’t directly advocate for seeking this out until we have human data on Rapamycin for aging, it is an option.
