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Down the Rabbit Hole: The genetics of exceptional longevity – Tom Perls

Tom Perls is a Distinguished Professor of Medicine at Boston University School of Medicine and an Attending Physician in Geriatrics at Boston Medical Center. He is among the international leaders that are contributing to our understanding of human exceptional longevity. Dr. Perls is the Founder and Director of the New England Centenarian Study, which is the largest study of centenarians and their families in the world.

Please note the transcript has been edited for brevity and clarity.

FLG: Hello, everyone, and welcome to the latest Down the Rabbit Hole interview. Today, we are joined by longevity expert, Thomas Perls, who is going to be talking to us about his area of research. So, Tom, if you could just introduce yourself and tell everyone a little bit about what you do as well.

Tom: Thanks very much Shannon. I’m Dr. Tom Perls. I’m a Professor of Medicine at Boston University School of Medicine and also a Geriatrician at Boston Medical Centre. I direct the New England Centenarian Study, which is the largest study of centenarians and their families in the world. I have been doing it a long time, we started back in 1995, at Harvard, and I have been at BU since 2002.

FLG: Why is studying ageing and longevity so important?

Tom: I think the best encapsulation of that is something called Geroscience. That was invented at the National Institute on Ageing. There’s actually a Geroscience working group that spans all the institutes so the National Institutes of Health. The premise is that if you can discover the basic roots or mechanisms of ageing, if you interrupt the process of ageing itself, if you slow it down, perhaps you won’t hit one disease that’s associated with ageing, but a whole range of diseases. You can actually do what happens in the centenarians, which is slow down ageing, and decrease the risk for ageing-related diseases and disability.

FLG: Why in society are we so obsessed with ageing?

Tom: Well, first of all, there’s marketing. I think especially in the 1970s and 80s, we really started to see some really pernicious, awful advertising about older people. Portrayals of them as frail, using walkers, and scared; promoting the ageism of “the older you get the sicker you get”. This advertising is itself a pernicious disease that skews people’s opinion of older people as diseased, dependent and a drain on society. These marketers want to scare the heck out of you, setting you up for their sales pitch that they can sell you their pill, injection, hormones, stem cells, etcetera, to stop and even reverse your ageing. Then, there is the cosmetic industry and medical spas, with their lotions and creams that make you look young again. The industry’s messaging may seem innocuous, but I think it can be really harmful.

The anti-ageing industry’s deceitful hucksterism has begun to backfire though as the 70 million-strong baby boomer generation in the US (14 million in the UK) are now in their mid-sixties to early eighties and they are resenting and resisting the demeaning messaging. I think for the most part for many of these individuals the goal is ageing well. Instead, people are wanting accurate and enabling views of ageing.

FLG: Do you think that had a negative impact on research in this area? Because ageing research is often referred to as a ‘quack science’, why do you think it has such a bad reputation?

Tom: I would say it’s not so much a negative impact as it is a distracting impact. Unsubstantiated claims funnel huge amounts of cash from well-meaning philanthropists and venture capitalists towards claims and promises that will never see the light of day. I am obviously not saying that there is not promising science that is worthwhile pursuing; just that human longevity research has always been vulnerable to sensational claims and with the current abundance of cash, that seems to be more prevalent than ever. 

FLG: Why are centenarians so interesting to study? How are they helping us to understand ageing-related diseases such as Alzheimer’s and cancer?

Tom: Well, it wasn’t always viewed that way. I think when we began the centenarian study, there was this idea that human ageing is so heterogeneous, and we all age so differently, that it was unlikely that anyone would find biological factors that were associated with exceptional longevity. It was really viewed as a stochastic, unpredictable phenomenon. Furthermore, ageing was just too complicated and therefore one would need huge sample sizes to try and find these factors that individuals who age very well may have in common especially compared to those who don’t age well.

Centenarian research in particular has greatly changed people’s minds about that. Studying lower organisms provides the advantages of researching genetically identical organisms under specific conditions and organisms with short lifespans so that experiments can be completed within days to a few years. Average people, with their substantial heterogeneity in how they age and their susceptibilities to ageing-related diseases are, relative to such lower organism studies, immensely more complicated. However, enrolling older and older centenarians, we began to notice that at the very oldest ages, they are increasingly alike in terms of their delay of or escape from ageing-related diseases and disability. With that homogeneity comes increased power to discover factors that these individuals have in common and therefore smaller sample sizes are capable of yielding significant associations.

FLG: What are some of the common qualities that they had?

Tom: First of all, let me set the stage in terms of how centenarians are demographically so unusual. Living to 100 is rare with one centenarian per 5,000 people in economically well-off countries. These people belong to the oldest one percentile of the population. But then living to 105 is a totally different ball game, so to speak, in that there’s a tremendous drop off in survival rate. The prevalence of centenarians ages 105+ years is approximately one in 250,000 people in the population and the top 0.1 percentile. It’s really a very different phenotype than living to 100. Then living to 110, again, is so very different, where those individuals, called supercentenarians, occur at a rate of one per 5 million and constitute the oldest 0.01 percentile. Supercentenarians are about a thousand times rarer than centenarians. These extraordinarily rare humans approach the limit of human lifespan which is defined by the oldest ever living human being, Jeanne Calment, who died in 1997, at the age of 122. 122 is obviously very different than 110, but for all intents and purposes, in terms of the very small number of people that we’re talking about, 110 really is approaching the current limit of human lifespan. At any one time in the USA, there are about 60 to 70 alive supercentenarians.

Of those who live to about 100, approximately 40% have at least one ageing-related disease before the age of 85. We call these individuals “survivors”, those who have survived to 100 with 15 years or more with one or more ageing-related disease that is normally associated with significant mortality; diseases such as dementia, cardiovascular disease, stroke, hypertension, diabetes and cancer. They’ve somehow lived with these diseases rather than die from them; they are resilient. Then, we have another 45% or so that don’t develop such a disease (or diseases) until after the age of 85 and we call this group, “delayers”. Finally, there’s the 15% of people living to 100 that we call “escapers”. They don’t have any ageing-related diseases normally associated with increased mortality. Sure, they may have slowed down a bit, although I know centenarians who have not. Some of them don’t even have chronic conditions that are not associated with increased mortality, such as cataracts.   

Now, you might say, if 90% of that sample has one or more ageing-related disease why would living to 100 be something one would aspire to? On average though, about 90% of the centenarians who survived to 100 were disability free at the average age of 93 years. They are living the vast majority of their lives independently, and compressing the time that they experience disability, even in the face of either being a survivor or delayer of disease. Then, they have difficulties only at the very relative end of their lives, which I would argue most of us would want. That is, to live a long life and compress the time you experience disability towards the very end.

Now, thinking about these different phenotypes, survival to 105 or to 110, we observe that clinical homogeneity that I previously mentioned. For example, the majority of supercentenarians are escapers, and they not only delay disability but also mortality-associated ageing-related diseases until the mean age of 106 years. This observation very much fits James Fries’ compression of morbidity hypothesis that he developed in 1980: As one approaches the limit of lifespan, you necessarily have to compress the time that you’re sick towards the very end of your life. To live to 100, this doesn’t appear to be the case, but compressing disability appears to be the norm. However, approaching the lifespan limit, again around 110 does seem to fit this hypothesis with regard to ageing-related morbidities. 

FLG: How are genetic tools and advanced technologies helping us to identify some of these genetic factors that are involved?

Tom: First of all, what’s so cool about the centenarians is that they are a human model of healthy ageing and resilience. They’re not a mouse model. They’re not a naked mole rat model. They’re not a Drosophila. They’re not C. elegans. They are a human model of markedly delaying or escaping ageing-related diseases. Also, they are not a disease model, they are a model of disease prevention. Therein lies the huge scientific interest in these individuals. Over the past 20 years, of course as Front Line Genomics has revealed countless times now, there is a revolution in our ability to discover genetic factors and their roles in disease. But what’s so cool about the centenarians, is that they are enabling our hunt for protective genes, not genes associated with disease risk.

We used to think that getting to be a centenarian entailed lacking disease associated genetic variants. Otherwise, how could you get there? Several groups now, including our own, have shown that but for a few exceptions with very modest effects, centenarians have frequencies of disease associated genetic variants that are similar to the general population. What likely sets centenarians apart are increased frequencies of protective variants, genes that are protecting against these disease-associated variants and also likely slow ageing and decreasing risk for ageing-related diseases. That’s a very optimistic genetic view of these centenarians. If it’s protective variants and therefore protective biological mechanisms, we may come up with drug targets that slow ageing, then that would be huge.

FLG: How much of an impact does our genetics play? And how much of an impact does our environment play? Because I can imagine, the environment has a big role, for example, you could have these protective variants, but if your lifestyle is obviously completely terrible, they’re not going to help that much.

Tom: You’re absolutely right. I think that there’s also another very optimistic view about the genetics of ageing, that comes from the study of Seventh Day Adventists that we’ve known for quite some time now. Seventh Day Adventists are quite a mixed group of people geographically, ethnically, culturally. They tend to have these extraordinary life expectancies. The women live on average to about age 89 and the men to about age 86. Average life expectancy in an economically well-off country is around 80-81. The very best areas like British Columbia in Canada have an average life expectancy approaching 83. What the Seventh Day Adventist study shows us is that, despite quite a mixed group of people, in terms of their genetic backgrounds, they’re still getting to these extraordinary ages. Why is that? It is probably because of the great health habits that the Seventh Day Adventist religion espouses. God has given them this incredible gift, an incredible body and lifespan that should not be squandered. Thus, the religion encourages a vegetarian diet, regular exercise, no smoking and no alcohol. They also emphasise lots of family and religion centered activities which may be conducive to better stress management. And lo and behold, they have these extraordinary life expectancies. So, what that says to me, is the vast majority of how you age is what you do with your environment, your health-related behaviours. If you do everything right, you can have these amazing average life expectancies of 86 as a man and 89 as a woman. Imagine that, that’s almost 30 years beyond the age of 60.

There’s also evidence that having these health behaviours allows you to delay ageing-related disease and disability. So instead of it being the older you get, the sicker you get, it’s much more the case of the older you get, the healthier you’ve been. This is an enabling and optimistic view of ageing that belies the pernicious, pessimistic false messaging of the anti-ageing industry. Now, if on the other hand, you do everything wrong, like smoke, drink too much, you are obese and you eat lots of meat and sweets and so on, then it totally makes sense that you’re going to pass away in your 60s and early 70s. 

Besides the Seventh Day Adventists there’s twin studies indicating that about 75% of the variation in what age we live to be, is going to be what you do with your health-related behaviours and about 25% is due to differences in our genetic blueprints. Now, that’s to live to 90. To live much beyond that, we and other groups are showing that combinations of genetic variants explain a greater and greater portion of survival with older and older age at death. For survival to around ages 105 and older, the tables are turned and about 75% of the variation in how old those individuals are living to is explained by genetic variation. And sure, smoking is very, very rare in those individuals, but for the most part, I think it’s also necessary to have some pretty rare and spectacular genetic signatures that are getting the people to those oldest ages.

FLG: If we could eventually harness these genetic factors in drug development, do we necessarily want everyone to be living into their 100s? Are these individuals genuinely happy and healthy? Also, what impact could that have on society?

Tom: First of all, that’s not going to happen. What’s not going to happen is the part about getting a lot of people to 100 or as some other people claim for that matter, living to 500. And there are people out there claiming that. They’re just nuts! Our aim with our research is to figure out how to delay or even escape diseases like Alzheimer’s and to enhance resilience.

FLG: I don’t want to live to 500!

Tom: This claim is just crazy. They don’t need to be claiming that kind of stuff to have this very optimistic view of ageing. I think the purpose of our research began with the observation that many of the centenarians have markedly delayed Alzheimer’s disease. We have about 5 million people in the United States with what I think is probably the worst disease, Alzheimer’s. With the baby boomers ageing, in such a large segment of our population, by around 2040, we’re looking at tripling the number of people with AD. So, it’s going to be somewhere around 15 million with Alzheimer’s, and that’s in the United States, of course, the same kind of epidemic is occurring around the world. So, the numbers are just huge.

If we can study centenarians to markedly delay Alzheimer’s disease that would be my dream come true. And it’s not just Alzheimer’s, it is the other ageing-related diseases as well and how to get people to markedly delay them towards the very ends of their lives. Does that mean we’re going to get a lot more people to 100? Maybe a little bit, certainly not much beyond that. But for the most part, what we’re shooting for is getting a lot of people into older age in good health and function, like the Seventh Day Adventists. If one can’t do it with healthy habits, maybe we can help them along with understanding some of these mechanisms that we believe could be drug targets, then develop drugs that do the same thing as to what is occurring naturally in these superagers.

FLG: What role do you think that gene editing technologies, like CRISPR, could play in this field of research?

Tom: I think mostly in understanding these mechanisms. There’s of course, I just read yesterday, that this whole field of reprogramming has captured the imagination of some extraordinarily wealthy people. This company that’s coming out called Altos Labs, that may or may not be funded by Jeff Bezos and a few other very, very wealthy people, offering extraordinary salaries to some individuals to lead some research efforts around reprogramming. I’m not going to say much more about the utility of that; obviously, some people believe that there probably will be some great things learned from this. As to whether that could lead to some individuals living to very old age in good health is a whole different ballgame. There’s always been a significant concern about when you start tinkering with the biology with some of these methods, you not only may slow down ageing, but you may also increase risk of cancer. So, people are being very careful, obviously, I hope. But we’re still very early in that game.

FLG: You are the founding director of the New England Centenarian Study. For those who don’t know, would you be able discuss what this project is exactly, and some of the main findings from it so far?

Tom: We’re primarily funded by the National Institute on Ageing. We have a number of studies, I’m one of the investigators for the Long Life Family Study, which studies about 550 families that demonstrate clustering for exceptional longevity. What do we mean by clustering? It is sib-ships in the oldest generation where there’s multiple brothers and sisters getting to extreme old age, and then we have also studied their offspring, and now we’re even studying their grandchildren. We follow the 5,000 family members that are enrolled in the study over time. This is a study that’s been going on since 2004. Our first wave of collecting data was from 2006 to 2009. As you can imagine, many of the oldest generation are now passed away. But we have a tremendous amount of data and are generating a tremendous amount of molecular data from the blood samples that we have been longitudinally collecting from all of these individuals. We’re currently in our fifth cycle of funding. We continue to collect a great deal of both phenotypic data and with the blood samples, we’re doing what I call ‘omic-ing’ the heck out of them. That is, we are not only generating whole genome sequence data but also the methylome, transcriptome, and also doing proteomics, and metabolomics. All these data will be freely available to qualified investigators on the NIH funded Exceptional Longevity Translation (ELITE) website. So, I think that the hope is that these data will go far beyond our shores, in terms of being of use to labs all over the world.   

The same thing is true for our other studies, which are the Integrative Longevity Omics Study, which is also studying families, but we’re really concentrating on these oldest individuals, those who are getting to 103, 104 and older. Also the Longevity Consortium Centenarian Project, same thing… collecting a huge amount of phenotypic data, and then ‘omics-ing’ the heck out of them, eventually making these data available to everyone who would like access to them. You have to do that. These are such rare individuals, they’re a gold mine that needs to be shared and hopefully by doing so, discoveries will be made much faster. With the AD epidemic growing and growing, we have no time to lose.

Then, finally, hot off the press is a study that we just had funded called RADCO, which stands for our study titled, ‘Resilience and Resistance to Alzheimer’s Disease in Centenarians and their Offspring’. In this study, we rely upon our other studies to find the centenarians that we call cognitive super agers. These are individuals who in their hundreds have the cognitive function norms of people in their 70s. They’re extraordinarily rare, but because we have these other studies going on, we can find them quickly and easily. Then, we collect a huge amount of phenotypic and molecular data on those individuals. We’re also performing cutting-edge MRIs and obtaining serum Alzheimer’s disease markers, like Phospho-tau217. P-tau217 has been shown to be practically as good as PET scans as a marker for Alzheimer’s disease. Then, a number of these individuals will eventually also go on to autopsy. We anticipate participants who have serum markers, MRI and/or neuropathological findings consistent with AD and yet they contemporaneously have or had excellent cognitive function. Those individuals are resilient against Alzheimer’s. And then we have those individuals who don’t have any of those markers and have totally clean brains at autopsy while again being a hundred or older. These study participants are resistant to Alzheimer’s disease.

One of the very cutting-edge things we are doing is providing blood samples from the centenarian cognitive super agers to George Murphy and his lab at Boston University’s Center for Regenerative Medicine (CReM) for the generation of induced pluripotent stem cells (iPSCs). George then differentiates these lines into muscle, liver and cortical neuron cell lines. George is conducting work to also differentiate these iPSCs into microglial and astrocyte cell lines. We then turn all our materials and resources over to Rudy Tanzi’s and Doo Kim’s laboratories at Massachusetts General Hospital and Win Hide’s lab at Beth Israel Deaconess Medical Center and we expect them to decipher the mechanisms that underlie resilience and resistance to Alzheimer’s. Rudy and Doo will use the cell lines produced by Dr. Murphy’s lab in their AD in a dish model to investigate mechanisms of resilience and resistance. So finally, rather than just typifying individuals with various omics, I think we’ve come up with a plan for getting at the biology and getting at the mechanisms and developing drug targets.  

FLG: It sounds so exciting. What do you think are some of the challenges that remain?

Tom: Sample size is a big deal. For complex ageing-related diseases, researchers believe that one requires tens of thousands of individuals to discover factors, whether they be genetic or otherwise, that are associated with these diseases. But as I’ve said, I think that the genetic component is so strong at these most extreme ages, you don’t need that many subjects. I think we’re talking about in the range of maybe low 1000s, maybe even fewer, especially if you’re talking about super- centenarians. It is with this smaller sample size that our analysis group, led by Paola Sebastiani, now at Tufts Medical Center, discovered genetic signatures composed of about 200 genetic variants that are highly associated with survival to age 106 and older. The association is lower for younger ages which speaks to the lower decreased genetic influence upon survival at younger and younger ages. It makes sense that so many genes are involved given the many different molecular mechanisms that have been found to influence ageing and its effects. Having just the right combination of variants to achieve these oldest ages is likely why achieving these ages is so very rare.

The other challenge is not just finding centenarians but finding centenarians with different genetic backgrounds. It’s really important that we collaborate with our colleagues in the Japanese centenarian study, the 100+ study in the Netherlands, several studies in Italy and elsewhere. In our conduct of RADCO, we make a concerted effort to enrol people of African and Latino backgrounds. The genetic signatures that enable survival to extreme ages are going to vary according to genetic background because of the environments that these different groups of people evolved in. It will be crucial to discover the determinant biological mechanisms that cross ethnic and cultural lines and those that are genetic background specific. By comparing and contrasting these groups, we’re going to learn much, much more about the biology. And also, if we want to come up with therapies, we may find that there’s going to be different therapies for different groups and different situations, which is the whole idea, of course, behind precision medicine. But I think that’s another really important challenge is getting enough people from different backgrounds as well.

FLG: Yeah, no, I agree. That’s really, really important. What do you think the future of this field will look like?

Tom: I think studying centenarians has provided quite an optimistic view of ageing. I think it’s a socially very important study. When you point out to society a bunch of people who are living to 100 and it’s an optimistic view of ageing, suddenly, people are pretty interested, at least in getting to age 85. It’s like a few people who are running a marathon. Not all of us can do marathons, but it makes us think we can all do 10Ks. And that’s what I think getting into your 80s is about. I have friends who bike, and when they ride with someone in their eighties, boy does that push them along!  So, I think that the studies of centenarians are socially, so very important and inspiring. I also believe that our studies are nearing a turning point for some major discoveries. I think we’re really going to start getting into the biological mechanisms and coming up with drug targets, which hopefully will yield therapies and strategies to help us be centenarian-like, like markedly delaying ageing-related diseases like Alzheimer’s disease.

FLG: Thank you so much for joining me today, Tom. It’s been really interesting. This field is becoming more and more important with the ageing population. I’m excited to see the results of all of the studies that you’ve got going on as well. So, thank you so much.

Tom: My sincere pleasure. Thank you for having me.