The Life Extension Revolution — Part 1

One truly serious problem of our time is death. It is because when time is up, time is up. You are no more. All your learnings, attempts, trials, errors, emotions, ideas, experiences, wishes, yearnings, dreams are no more. No matter how large your desire to live, you will not live. really There are no second chances. And you will never add to the Great Ledger. “Now discontent nibbled at him — not painfully, but constantly. Where does discontent start? You are warm enough, but you shiver. You are fed, yet hunger gnaws you. You have been loved, but your yearning wanders in new fields. And to prod all these there’s time, the bastard Time. The end of life is now not so terribly far away — you can see it the way you see the finish line when you come into the stretch — and your mind says, “Have I worked enough? Have I eaten enough? Have I loved enough?” All of these, of course, are the foundation of man’s greatest curse, and perhaps his greatest glory. “What has my life meant so far, and what can it mean in the time left to me?” And now we’re coming to the wicked, poisoned dart: “What have I contributed in the Great Ledger? What am I worth?” And this isn’t vanity or ambition. Men seem to be born with a debt they can never pay no matter how hard they try. It piles up ahead of them. Man owes something to man. If he ignores the debt it poisons him, and if he tries to make payments the debt only increases, and the quality of his gift is the measure of the man.” — John Steinbeck What does it feel like to know you’ll end? That you end like this: That everyone you love ends like this: That everyone — every human being ever — either ended like this or will end like this. That * every species’ ends like this: almost *I said “almost” because there are some species that have been around for a long time and there are some species, for example, hydra , who don’t seem to die from aging at all. There have been very few exceptions — and there have been no human exceptions. Every human is vulnerable. Every human has fallen off The Ultimate Cliff. Every human who inspired you, every human who frustrated you, every human who fought for ideals you hold dear, every human who destroyed those very ideals, every human who helped you understand our place in the universe, every human who served as your moral compass, every human you love(d) so much that you would gladly lose yourself for them, every human who would do the same for you, and every human who ultimately added to the Great Ledger — every human ever — has either fallen off The Ultimate Cliff or will fall. Everyone died or will die — that the norm. is Unless we do something. And life after death seems like nothing more than just another one of our deepest yearnings. It probably feels sad and scary to be getting closer to The Ultimate Cliff — but then why aren’t you scared? feeling Because you most likely don’t really that cliff or think of it as The Ultimate Cliff. You there is a cliff…somewhere…down the road…but far away from and you are right at this moment. And you can’t imagine non-existence so it’s probably meaningless to you. see know where when Here’s how you actually see it: But you are wrong. You eventually face The Ultimate Cliff and you end. will will Furthermore, what if I told you that you are carrying a inside you which self-destruct in 1 week, or 1 month , or 1 year — and you will not have a choice. Now imagining your end isn’t that hard because I just ruined all your plans. time bomb will And that’s why you should think about the problem seriously — you are indeed carrying a ticking time bomb. “And you run, and you run to catch up with the sun, but it’s sinking / Racing around to come up behind you again / The sun is the same in a relative way, but you’re older / Shorter of breath and one day closer to death / Every year is getting shorter; never seem to find the time / Plans that either come to naught or half a page of scribbled lines…” To live or to die, to age or not to age Another truly serious problem — that inevitably leads to death — is aging. I believe humanity have a choice — to live or to die, to age or not to age. And we should have this choice possible. should as early as Some of you will think, “I am fine with death. I don’t want to live forever. Anyway, there is no such thing. (And even if there was, I don’t want it.)” Ok, your choice. But the rest of us should at least have to die, or at least to not die 120 years of being born. Or an option to to live longer. an option not within choose Our world is so precious and our human species even more so. There is so much to know: are we alone? will we create sentient beings? when do we finally colonize another planet? when do we achieve interstellar travel? do we transcend our human condition? do we ever become digital (or some other form)? do we ever truly understand one another? does it become possible to time travel? can we jump universes? and so much more. We got this extraordinary opportunity called life — non-existence and death norms, not life, so life is precious. There is so much we can add to the Great Ledger. But we time. are that need We need time — may be extra 10 years, 30 years, 200 years, 500 years or 1000 years or 100,000 years or longer? Who knows. All we can say is that as of now, we can’t (yet) opt-out of death. Some of you will think “I don’t want such a long life! I want a life, one without pain and suffering.” You are saying this because you are imagining a (long) life which is a simple extension of your aches and pains either you’re imagining your current state for a very long time or you’re imagining deterioration that comes with age. That’s why you say you want a good quality of life, if it’s short. You don’t want to suffer for hundreds or thousands of years! And you would be right — but because you’re picking one the other. We should have . good current — even only over both Think of it this way: That self-destructing time bomb I mentioned earlier? Well it inside of you. And if you’re reading this, then it’s already ticking and it self-destruct one day. I bet most of you will not want it to self-destruct tomorrow or next week, especially if you are healthy, happy, and satisfied. is will Now, would you want it to self-destruct one year from now? Ten years from now? Probably not if you are still healthy, happy, and satisfied. Twenty years from now? Probably not if you are healthy, happy, and satisfied. I think you get the pattern. You may not know much time you , but you still don’t want that bomb to self-destruct . how want anytime soon The worst part is — the probability of the time bomb self-destructing after a certain age. The longer you live, the higher the chance of the bomb going off. And the harder to stop the bomb. grows exponentially Most of us will disagree about how long we want to live, but we will all agree that we all want to live a healthy life. Now, what if I told you this: science can give you a healthier life and in doing that, science can give you a longer life. There is no way to extend the lifespan of a sick person. Really sick people usually die, sooner rather than later. Living longer will occur as a of living healthier. simultaneously side effect In some sense, this has been the case so far — we have already extended life — we live almost twice as much time as people did in the early 1900s. That’s incredible! We’ve gone from an average life expectancy of around 47 in the 1900s to around 77 today. We got an average of 30 years more and none of us want to give this time back! But we’ve paid a different price for it — aging. And aging sucks. And we also can’t opt-out of aging (yet). Aging brings a variety of chronic conditions and diseases that we don’t have to deal with when we’re young. We start with minor aches and pains. Soon the cushioning of our joints is thinner, our eyesight is blurry, our kidneys are less effective, our hearts are weaker, our immune systems are weaker, leaving us prone to infections that probably couldn’t have touched us earlier. Inevitably these minor aches and pains deteriorate into chronic conditions and diseases. Diabetes. Cataract. Osteoarthritis. Heart disease. Cancer. Alzheimers. Stroke. And more. We got years to live, but we also got a whole bunch of chronic diseases that go with these extra years — and these illnesses rob us of a good quality of life. A lot of people currently spend their last 10–15 years of their lives in pain and misery due to illnesses. more Many of these age-related diseases (for example, Alzheimer’s) don’t have effective treatment options. Others, such as high blood pressure, stroke, or heart disease, require continuous monitoring and medication, costing us tremendous amount of money and grief. Aging is natural — why not just cure all those diseases? — “Every man desires to live long, but no man wishes to be old.” Jonathan Swift Here’s the most important point: We know that the elderly have a higher rate of chronic degenerative diseases than the young. But that’s the biggest problem. The real problem is the between aging (as a whole) and diseases — an individual’s risk of diseases with age — and these diseases eventually kill — and this is the root problem. not relationship rises exponentially Aging the self-destructing time bomb. is For example, we know heart disease is the number one killer in the Western world. So, we’re trying to develop ways to solve this problem. Let’s say we can prevent heart disease — then yes, it save all those people who have heart disease. But if those individuals are older in age, then it save them for long — it doesn’t do much for them in terms of giving them many more years — it won’t necessarily extend those individuals’ (# of years) by much. This is because an elderly individual who no longer has heart disease would only get a few healthy years before another disease kicks in — cancer, Alzheimers, etc. — because each year, this individual’s risk of diseases increases (most times exponentially) with his age. will won’t that healthy healthspans healthy In short, attacking diseases separately for the elderly means taking whack-a-mole approach — you’re just swapping heart disease for some other disease a few years later. Attacking individual diseases basically means attacking symptoms without attacking the root of the problem. It is far better to attack aging as a whole**.** Solving aging be prioritized — because that gives us more time better health. Because a side effect of aging is that these diseases are either cured or under control. And we would live longer. Now, do the earlier questions seem so unreasonable? must and undoing that is why If we all want to live healthy, which means we all want science to cure diseases like cancer, heart disease, diabetes, Alzheimer’s, and thousands other diseases, then (and perhaps even death)? So even if you only care about health and not longevity, it makes sense to try to solve aging — unless you think giving older people more (healthier) years is not a worthy endeavor. it makes most sense to try to solve aging still more And all this isn’t science fiction. With new approaches and technologies, we may be in a position to improve our health drastically and as a result extend our lives drastically. finally Aging seems to be a treatable (and hence solvable) problem. (Death, I hope, is as well.) What we need is for many more of us to think, advocate, and work on the problems of aging and death seriously — we need to architect, augment, and accelerate approaches that attempt to solve the problem of aging (and hopefully death). Aging: inching closer to The Ultimate Cliff The immortal Gods alone have neither age nor death! All other things Almighty Time disquiets” — Oedipus by Sophocles Everyone is aging. The process of aging has two major components: 1) how long an organism lives and 2) the physiological deterioration (known as ) that characterizes old age. senescence And all aging eventually leads to death. Sooner or later the bomb self-destructs. The Ultimate Cliff always shows up. . Always It’s strange how we talk about aging, but most of us don’t really understand what aging . We (sometimes) we’re getting older, but we don’t really know the processes that drive aging. is realize So let’s first see what happens to us as we age. What happens to you as you age? Trillions of cells in your body (more than 37 trillion cells!) are changing — some are dying, some are getting destroyed, and some are forming. But cells in your body are constantly changing. In humans, aging represents the of changes , these changes are at the molecular and cellular level and have physical, psychological, and social impact. Majority (or at least a significant proportion) of humans experience the following symptoms of during their lifetimes (and many more): accumulation over time aging Young — teens Young children have the ability to hear high-frequency sounds above 20 kHz. Teenagers lose this ability. 20s In your mid-20s, cognitive decline begins. If you are a female, your fertility peaks in the mid-20s, and then decline begins. In your 20s and 30s , you start developing wrinkles. 30s From 30–70, your body mass starts to slowly decline. Your ability to focus clearly on close objects worsens after 35. 40s and 50s You will need reading glasses by age 45–50, if not earlier. Around age 50, if not earlier, your hair starts to turn grey. By 50, 30%-50% of males and about 25% of females notice hair loss. If you are a female, menopause will typically occur between 49 and 52. 60s and early 70s In your 60–64 years of age, the incidence of osteoarthritis rises to 53%. About 20% will report osteoarthritis at this age. disabling , which leads to cardiovascular disease (for example stroke and heart attack) and globally is the most common cause of death, is classified as an — this is because symptoms, if they occur, do not usually begin until middle age. Atherosclerosis aging disease Dementia becomes more common with age. About 3% of people between the ages of 65 and 74 have dementia. Furthermore, many types of memory decline with aging. Most patients with demential have no family history and as high as 95% of cases could arise from spontaneous mutations — result of cellular aging. Mid 70s and mid 80s Almost half of people older than 75 have hearing loss, inhibiting spoken communication. (Many vertebrates such as fish, birds and amphibians do not suffer from this in old age as they are able to regenerate their cochlear sensory cells, whereas mammals including humans have genetically lost this ability — thanks evolution.) Dementia becomes more common with age. About 19% between 75 and 84 have dementia. Nearly half of those over 85 years of age have dementia. By age 80, more than half of all Americans either have a cataract or have had cataract surgery. Frailty, defined as loss of muscle mass and mobility, affects 25% of those over 85. causes vision loss and increases with age, affecting nearly 12% of those above the age of 80. This degeneration is caused by systemic changes in the circulation of waste products and by growth of abnormal vessels around the retina. Macular degeneration Oh wait, I didn’t add these: There are changes to the brain: as we age, there is a . loss of white matter Age can result in visual impairment — so non-verbal communication is generally reduced, leading to isolation and possible depression. The maximum human lifespan is suggested to be 115–120 years “ ”. The oldest reliably recorded human was Jeanne Calment, who lived until 122 years (and 164 days) and died in 1997. for the foreseeable future Chronic conditions account for about 80% of total health care expenditures in the US and approximately 80% of older adults have one chronic disease, and 68% have two or more. Thanks biology. Thanks evolution. Thanks nature. Thanks society. Becoming old also brings a lot of advantages — people have more time, more experience, more knowledge, more perspective, and important relationships. Many positive social and financial things happen over time, but the biological deterioration and chronic diseases make it hard to enjoy these for long. Some positive things: too The truth is that aging is among the greatest known risk factors for most human diseases: of the roughly 150,000 people who die each day across the globe, about 100,000 die from age-related causes. The worst part: As Aubrey de Grey says, “ it’s about thirty World Trade Centers, sixty Katrinas, every single day”. That’s scary. Insanely scary. So scary that it unacceptable. should be In industrialized countries, this number is even higher — something around 90% of people die from age-related causes. Yes, this bucket is broad, but that’s because aging comes with a broad range of deterioration. In short — remember — mortality risk rises with aging! At this point, you might be wondering “ ” Ok, all this scary stuff happens in my body, and as a result my body and mind get weaker and then I die…[panic a bit or panic a lot]…um…it doesn’t sound so great, so why do we even age then — why didn’t evolution just weed it out? Does everyone [you mean every species] experience this or is it just me? And does everyone die as a result? How do we age again? Can’t someone stop this? Good questions. Let’s get some answers. Gerontologists (folks who study aging and age-related diseases) think about these questions (well, not specifically about stopping aging for you (or me), but for all of humankind). And the approaches to understanding aging can be divided into two very broad categories: those that try to answer the question “Why do we age?” and those that try to answer the question “How do we age?” _Wait…_but you don’t really know how to think about aging so let’s work on that first. Understanding Aging: Some high-level stuff A multicellular organism is able to exist for only so long. Then the organism begins to age — and it begins to deteriorate. In this sense, aging of any organism is to time — the deterioration is — its physiological functions necessary for survival begin to deteriorate time. related over time over [In another sense, aging doesn’t to be to time. If you think about it, time continue, but occur. What I mean is, suppose you’re a 60 year old, but you’re very healthy and your body is as good as a 45 year old’s body instead of an average 60 year old’s body. This means chronologically you are 60, but biologically you are closer to 45, i.e. your mortality rate is not higher at 60 than it was at 45. [I’ll talk about this in the context of mortality rate later.]] need stuck can deterioration doesn’t have to Over time, humans came up with many theories about aging — ranging from depletion of something called “life force” to accumulation of simple wear and tear and damage. But throughout our history, there haven’t been that many theories about aging. In fact, even at the beginning of the 20th century, the biology of aging was still mostly unknown. concrete It was the discovery of DNA in the 1950s that opened up new formulations around the genetic basis of aging. In the 1950s, the free-radical theory of aging — the first molecular theory of how aging occurs — was first put forward; this talked about aging as being a result of of molecular damage. In the mid-1950s, it was suggested instead of attacking each disease associated with aging individually, we would have most success if we attacked aging as a whole — that was 60 years ago! In the 1960s, many publications started talking about the role of telomere length in diseases. In the 1970s, National Science Foundation (NSF) funded a 3-year project on the future of aging, which resulted in book titled — this was one of the first times delaying aging was discussed formally. Over time, people began to develop theories on the causes and processes of aging. accumulation Human Life Span: Social Policy and Social Ethics By the end of the 20th century, gerontology, the study of aging, and geroscience, the interdisciplinary field that tries to understand the relationship between aging and age-related diseases, had come into their own. These fields are relatively new, but have made incredible progress over the last several decades. This summer (2018), the World Health Organization (WHO) took an important step toward better understanding aging by adding an extension code for “ageing-related” disease to its , or ICD-11. 11th revision of the International Classification of Diseases for Mortality and Morbidity Statistics In WHO’s ICD-11, the extension code for is defined as “caused by pathological processes which persistently lead to the loss of organism’s adaptation and progress in older ages.” “ageing-related” This was a result of a submitted to the WHO’s ICD-11 Task Force by researchers from the Biogerontology Research Foundation, the International Longevity Alliance, and the Council for Public Health and the Problems of Demography. joint proposal “ ” John Beard, MBBS, Ph.D., director of WHO’s Department of Ageing and Life Course. “ ” [can’t wait to see the data over the next few years.] The ‘ageing-related’ extension code gives the opportunity to link various outcomes to aging-related causes, said It will be interesting to see how widely it is applied. As mentioned earlier, the process of aging has two major components: 1) how long an organism lives, 2) physiological deterioration (known as ) that characterizes old age. senescence At a very high level: Aging over time — these include damage, accumulation of waste, errors and as well as the responses to them. These processes result in the signs of aging we’re already familiar with (grey hair, wrinkles, join pain, etc.) and gradual deterioration, which ultimately leads to age-related diseases that kill us all — aging always leads to death. This characteristic of aging — the gradual deterioration leading to death — is known as senescence. is a series of processes Aging can refer to both single cells that have ceased to divide ( ) and to the population of a species ( ). cellular senescence population aging Aging can be thought of as vs. : actual number of years you are now (say, 60 years old — you’ve existed for 60 years) vs. internally how old your body is (say, 50 years old — the health indicators of your internal body show that you’re younger). chronological aging biological aging Keep these points in mind as you read the next few sections. Now back to your earlier questions: Does every species age? Does every species die as a result? Why do we even age? How do we age? Can’t anyone stop this? Does every species experience aging or is it just us? who ages and who doesn’t? (and who dies and who doesn’t?) First: Almost all species age, and almost all species die. But some . don’t fission to produce daughter cells, plants grow runners to produce clones of themselves, have a regenerative ability and do not undergo senescence, and flatworms appear to regenerate (i.e. heal) indefinitely. Some species can be considered immortal : bacteria strawberry Hydra s planarian How can you think about this? Remember the distinction between chronological age vs. biological age? Well, in these biologically immortal species, these two are senescence and thus age-related diseases have been delayed in these organisms. Sure they’re getting older, but the usual deterioration characterized by aging, which ultimately results in death, has been (and may be delayed indefinitely some organisms). decoupled: chronologically delayed Earlier we said mortality rate increases with aging (in senescent organisms), but if the mortality rate of the species does increase after maturity, we say that the species does not age and is thus decoupling mortality rate from chronological age. not biologically immortal — Why use this definition and not the comic book / movies definition of immortality (that of being )? Because even a biologically immortal organism _can still die (_from means other than senescence) — it can still die from falling off a cliff, getting run over by a vehicle, or earth getting destroyed by asteroids or a billion other ways. completely indestructible So strictly speaking, if we use our superhero definition, no species is indestructible or lives forever — no one is immortal. But if we think of it biologically, then some species are immortal — they don’t deteriorate over time (like we, and most other species, do). Their risk of death stays low and constant throughout their existence — this is the next best thing. They do not experience deterioration that characterizes aging. Next best thing: some species are negligibly senescent . According to the , the following organisms have negligible senescence, i.e. they appear not to age: Animal Aging and Longevity Database ( ) — 77 years Blanding’s turtle Emydoidea blandingii ( ) — 102 years Olm Proteus anguinus ( ) — 138 years Eastern box turtle Terrapene carolina ( ) — 200 years Red sea urchin Strongylocentrotus franciscanus ( ) — 205 years Rougheye rockfish Sebastes aleutianus ( ) — 507 years Ocean quahog clam Arctica islandica ( ) — 5,062 years Great Basin bristlecone pine Pinus longaeva It seems that aging is inevitable. not These species age , i.e. they can become 50 years, 100, years, 500 years, or whatever (that’s how long they’ve existed so far), but they don’t necessarily age (or age as fast) , i.e. they don’t deteriorate from aging. Note that the lifespans of these organisms vary, but none of these species experience deterioration. chronologically biologically But…here’s the problem: Each organism listed above (including a biologically immortal organism) from means other than senescence — it can still die from falling off a cliff, getting run over by a vehicle, or earth getting hit by enough asteroids to be totally destroyed or a billion other ways. can still die Senescence is the inevitable fate (as of now) of all humans. We’re not biologically immortal. And if that is not bad enough, some rare human mutations can cause . Thanks nature. None of the organisms listed above are humans. accelerated aging diseases But…before you get too depressed, here’s some hope: The above list of long-lived species shows that living organisms live very long (or what we would currently call very long), without facing deterioration of old age. That an individual tree has lived for more than 5000 years says that there may be some fundamental limitation on how long an individual living organism can live (or that limit is 5000 years). can not at least May be potentially immortal species such as about delaying senescence (and hence about death from age-related diseases). Hydra can tell us Senescence, in some species, can be actively delayed! Scientists have shown this. In 1934, it was discovered that can extend lifespan by 50% — but wait — in rats! Not humans. But still. (This was controversial because some studies showed a significant effect, while others did. Some studies in monkeys show that calorie restriction has positive impact on ’ health and some claim even on longevity. In any case, scientists now do think that calorie restriction has a positive effect on health.) calorie restriction monkeys Something incredible happened in the 90s — scientists found that a single mutation in a microscopic worm could double its lifespan. Again, not humans, but still… Also, in the last 15 to 20 years, scientists have identified a whole series of pathways that are really key in regulating how we age. (More on this later). Even in humans, there are some cells with the such as 1) cancer cells which have lost the ability to die, such as the cell line (it is the oldest and most commonly used human cell line — it was derived from cervical cancer cells taken on February 8, 1951 from ), 2) certain type of , such as (producing and ). These remain immortal for as long as we are alive and even after we die, they can continue replicating in labs! potential for immortality, HeLa Henrietta Lacks stem cells germ cells ova spermatozoa In summary, 1) there species that do not age, 2) in some species that do age, — and hence , and 3) some species (hydra) are already they have the capacity for indefinite self-renewal. are senescence can be delayed healthspan and lifespan can be extended immortal — While it is true that researchers have a long way to go before they can reduce or eliminate senescence, these cases give us reasons to be optimistic. human As noted earlier, for most species, the mortality rate of the species increases with aging. And we said if the mortality rate of the species does increase after maturity, we say that the species does not age and is said to be Now, if this mortality rate remains constant, this rate determines the mean . The lifespan can be long or short, though the species technically “does not age”. Check out Wikipedia’s )). not biologically immortal. lifespan List of longest-living organisms Let’s dig into longevity and lifespans a bit more to better understand this. what about longevity? who’s living for how long? Second: Longevity can be thought of as — the amount of time a member of a species can be expected to live. Lifespan is longest time the species is of living — upper limit at the species level. life expectancy capable and life expectancy are tied. Mortality rate How you can think about this: life expectancy, at any given age, is the average number of years a member of a group if their mortality rate for remainder of their lives stayed the same as their current mortality rate. would continue to live Let’s look at this (read the wonderful presentation by ): chart Max Roser in Our World in Data Source: (check out the website — it’s interactive. Side note: notice the the high mortality of the 1918 flu epidemic in UK and of 1945 in Japan) — life expectancy drops sharply) Our World in Data This chart shows life expectancy at birth — from 1543 until 2013. For most of the period, only data from UK is available. Look at that incredible increase in life expectancy over the last century. In 1550s, a newborn was expected to live only until 25–40 years. And today, he would be expected to live between 65–85 years! Let’s look at England — for which there is longest time-series data. Source: Our World in Data Before the 20th century there was no trend for life expectancy: life expectancy fluctuated between 25 and 45 years. In fact, this was the case for a before the 20th century. long time Note that this is nuanced (apart from a) how good the data is, 2) how small the sample sizes were, 3) how this expectancy was modeled): In 1850 a newborn was expected to live around 40 years (red line). Now, if he made it to 5 years of age, he was expected to live about 45 more years (yellow line) — making his life expectancy around 50–55 years! This shows that child mortality rates were very hight back then (child mortality is defined as the number of children dying before their 5th birthday). If a child makes it to his 5th birthday, his prospects of surviving improve quite a bit. Next, if he made it to 10 years of age, he was expected to live 45–50 more years — making his life expectancy about 55–60 years. (light green line). Again, if he made it to 20 years of age, he was expected to live 40 more years — making his life expectancy 60 years. And so on… Here’s the take away: In 1850 a newborn was expected to live around 40 years (red line)…but , individuals who lived to adulthood (that is at least 20 years of age), then could end up living between 60–80 years! if infant or child mortality is subtracted Notice the drastic increase in life expectancy at age 0 between 1850s and 2011. What’s happening? In the 1850s, the average life expectancy at birth was about 40 years (red line). In 2010, the average life expectancy at birth was about 75–85 years — an increase of 35–35 years! In 1850 a 5-year old was expected to live about 55 years. In 2013, a 5-year was expected to live a little over 80 years — that’s an increase of 25 years. Back then, life expectancy changed dramatically after childhood — there was a dramatic increase in life expectancy once adulthood was reached. This was largely because back then, young children died from all sort of diseases that we now know how to cure — medicine and scientific knowledge have lowered the risk of death of young people. In our current time, life expectancy at birth is very different than life expectancy after childhood — this is largely because we have drugs, therapies, and cures for most diseases that young people face. not Next, notice the somewhat impressive, but not-nearly-as-drastic increase in life expectancy at age 70 or 80. What’s happening? In the 1850s, if an individual made it 60 years of age, he was expected to live to about 73 years (dark blue line), and if he made it to 70, he was expected to live to until a little less than 78 (purple line). In 2013, if an individual made it to 60 years of age, he was expected to live to be around 83years and if he made it to 70 years, he was expected to live to 88 years — an increase of about 10 years! This increase is quite a bit, but not as drastic as the increase in life expectancy at birth — this is because . As you get older, you’re essentially swapping out one age-related disease for another. The risk of disease rises exponentially with age. In this sense, fighting individual age-related diseases is a losing battle — curing individual (aging) disease only adds two to three years of life before another aging disease hits. aging still kills any But it true that there have been improvements in survival after age 65 and this has led to the rise in the length of people’s lives. So even though getting a handle on aging and age-related diseases has been hard and slow, we’ve made quite a bit of progress. More people live longer now than earlier. is We’ve increased the percent of people who live longer and longer. Let’s look at another chart. Source: (Note that, less than 50% of the people born in 1851 in England and Wales made it past their 50th birthday. But by 1911, a little over 70% of people made it past their 50th birthday. And more than 95% of the people born in England and Wales today live longer than 50 years.) Our World in Data This chart shows the percent of people who are expected to survive up to and beyond various successive ages in England and Wales. Note that, less than 50% of the people born in 1851 in England and Wales made it past their 50th birthday (see where the 1851 line crosses 50 years of age). But by 1911, a little over 70% of people made it past their 50th birthday. And more than 95% of the people born in England and Wales today live longer than 50 years. This says we have been delaying mortality! (Yes this data is only for England, but trends in many other places look similar.) Longevity is something scientists and the medical field have influenced greatly. Life expectancy has steadily increased — it has been an extraordinary human achievement — . one of our greatest achievements This incredible achievement by scientists and the medical field brings up a question: is human life expectancy approaching its limit? Is there an upper limit on the human lifespan? This question has been asked again and again throughout history. Over time, many people have said that life expectancy is close to this maximal limit and these experts have repeatedly been proven wrong. For , a crude calculation made in 1928 indicated that the average human life span would not exceed 64.75 years. At that time, life expectancy in the United States was only 59.4 years. What was not considered was the fact that Australia, by then, had already achieved a life expectancy of 62.83 years. In 1990, it was again projected that the life expectancy 50 year olds could not go beyond 85 years, but Japanese females surpassed that limit in 1996. example Mortality been postponed and life been extended! In this sense, we’ve continuously been working on life extension. has has And this has been a result of improving overall health — we have not even attacked aging as a whole . , in some sense, human senescence has been delayed. But the argument is that by attacking aging as a whole (and hopefully eradicating it), we can buy more time and better health. yet Even then even even what about maximum lifespan? is there a limit, and if yes, then can’t we live longer than that limit? Third: Life expectancy differs from . Life expectancy is an average for all people in the population — including those who die as infants and children, those who die in early adulthood, those who die in middle age, and those who live until old age. Maximum lifespan, on the other hand, is an upper bound of life. The maximum number of years any human has lived is 122. There have been many examples of people living significantly longer than the life expectancy of time period: maximum life span their Many of these people (and others) outlived most of their ancestors. They lived until “old age” when old age wasn’t the norm — they probably survived dysentery, smallpox, pneumonia, typhoid, malaria, flu, and many other infections. It turns out that species age at different rates. And maximum lifespan is determined by the . Maximum lifespan is the maximum amount of time one or more members of a species have been observed to survive. The apparent maximum human lifespan limit is 125 years of age (the longest a person has lived is 122 years). rate of aging Most living species have at least one on the number of times the cells can divide. (This is called the , although the number of cell divisions does not necessarily control lifespan). In any case, aging and lifespan vary greatly between species, even very similar species. upper limit Hayflick limit For example, a mouse does not live more than 5 years yet humans can live over 100. A mouse, therefore, is considered elderly at 3 years while a human is elderly at 80 years. Mammal lifespans also vary significantly — (oldest mammals) have been estimated to have lived at least to 211 years of age, while the shortest-lived mammal was a mouse that lived for ~0.8 years. bowhead whales And there may be no limit to the lifespan! Hydra’s Source See if you’re interested in the maximum life span of species. AnAge (Animal Aging and Longevity Database) These differences in life span between species are thought to be a result of genetics, but they are still a puzzle. Here’s where it gets really interesting and where the previous part is used: According to , the probability of a 20-year-old male dying before his 30th birthday is 1.1% and for a female it is 0.4%. However, the risk of a 60-year-old male dying before his 70th birthday is 15.3% and for a female it is 10.8%. And the risk of an 80-year-old male dying before his 90th birthday is 70% and for a female it is 58%. US social security data What does this mean? This means (what we said earlier), as you get older, the risk of dying increases. Mortality risk does not stay constant — it increases with age. And it increases with age of age-related diseases. because But here’s the hope — here is what the community is trying to do: they’re trying to keep this risk low (mostly) constant. This risk increases with your age — and as of now, your age = your chronological age = your biological age (mostly). But now if we can let your chronological age increase, while keeping your biological age low (and near constant), then this risk of death would increase (or would not increase enough to affect you very much). If we could somehow keep this risk low constant life, then the average person would live for a long time, may be 1000 years (or more). and not and throughout For example, earlier we saw that the probability of a 20-year-old male dying before his 30th birthday is 1.1%, while the risk of a 60-year-old male dying before his 70th birthday is 15.3% and the risk of an 80-year-old male dying before his 90th birthday is 70%. But now suppose we could attack processes that cause aging (and hence age-related diseases) so that we can keep this risk of death at any age around 1.1% (or even if is not constant, it would increase very slow), then the risk of a 60-year-old male dying before his 70th birthday would also be around 1.1% and similarly for an 80-year-old and a 90-year-old, etc. That’s the goal. The argument is this: The apparent maximum lifespan limit of 125 years is tied to our current risk, Our current risk is tied to age-related diseases, Our age-related diseases are a direct result of aging, So let’s try to eradicate aging (as a whole) to lower this risk and push human lifespan past this apparent limit. In part 3 of this series, I’ll talk about several approaches to do this. A few points to note (and why this isn’t that simple, but worth all the effort, in my opinion): Researchers have long debated whether humans have an upper age limit — no one knows. The consensus in the field is that the risk of death starts increasing in adulthood, up to about age 80 or so. BUT after this everything is unclear — there’s massive disagreement about what happens as people enter their 90s and 100s. Death rates seem to level off in late life. Death rates are still pretty high though. AND because death rates seem to level off in late life, some people say that there is no fixed upper limit to human longevity, or fixed maximum human lifespan. A quick side note: death rate is just one metric that scientists used to get a handle of maximum human lifespan. Another suggested metric is a person’s value (a measure of the volume of oxygen flow to the cardiac muscle), which decreases as a function of age. Therefore, the idea is, that your maximum lifespan could be determined by calculating when your VO2max value would drop below the metabolic rate necessary to sustain life (which is approximately 3 ml per kg per minute). I need to read more about this (and other potential proxies for maximum human lifespan), so once I do that, I’ll come back and update this part. VO2max Below is a detour for the curious reader, feel free to skip_*_ it to go the next section titled “Why is this (aging) even happening to you?” brief *But, honestly, if you’re already reading a 50+ minute article, then you might as well take out another 3–5 minutes. I promise it’s cool. For the curious reader: : A story about the . First world’s oldest person In 1965, a 47-year old lawyer, Andre-Francois Raffray, thought he had made a great deal. In exchange for the ownership of her apartment, (about $500) per month until she died — at which point he would get the apartment. he agreed to pay a 90-year-old woman 2,500 francs She was born on February 21, 1875, about 10 years after Abraham Lincoln was assassinated. When she was around 12 years old, she met Vincent van Gogh, who visited her father’s shop. She married in 1896 — when she was 21. She outlived her only child, a daughter who died in 1934. In 1942, her husband ate cherries that were treated with copper sulfate; he developed jaundice and died of poisoning after one and a half months. She had eaten fewer of the cherries and survived. She also outlived her only grandson, who died in 1963. And yes, she outlived the lawyer Andre-Francois Raffray. He died Christmas of 1995 — at age 77 — soon after 120th birthday! By that time he had paid three times the worth of the apartment! her She died on August 4, 1997, when she was 122 years 5 months and 14 days old and she is believed to have been world’s oldest person. , based on your age group. Causes of death are ordered by rank. Second: How you are (most likely) going to die Source unintentional injury (accidents), suicide, cancer Early teens: — accidents, suicide, and homicide. This means if you survive young age, you’re at low risk of dying from diseases, at least for a while. Late teens — early 30s: All external causes accidents, cancer, and heart diseases. According to as much as 4% to 10% of all heart attacks occur before age 45, and most of these in men. And about 4% of cancers are diagnosed before age 39. Oh gosh — this is where the scary stuff starts. Late 30s — early 40s: Harvard Medical School cancer, heart disease, accidents. Notice that the ordering has changed. Notice that until early 40s, accidents are the leading cause of death. In your late 40s, you’re more likely to die from diseases than accidents. Late 40s — early 50s: cancer, heart disease, accidents. There’s a difference between . Men are most likely to die of cancer, while women are about as equally likely to die of cancer as they are of circulatory diseases. Late 50s — early 60s: what kills men and women in their 60s heart disease, cancer, chronic lower respiratory disease. 65+: Your of getting rarer cancers, such as throat, esophagus, kidney, and pancreatic cancers, is higher in your 70s ; the risk of cancer peaks in your 70s. Men are at risk of prostate, colon, and lung cancer and women are at risk of breast, colon, and lung cancer. 70s: risk People 80 years and older have around 40% chance of dying from a heart disease. We would think it’s due to cancer, but surprisingly it’s heart disease. 80s: (Interactive) Source I know it’s hard to read, go to the source — it’s worth it. Source : : What does life expectancy look like across the world? It varies, quite a bit. Third Life Expectancy World Map of Life Expectancy in 2015 (Source: Max Roser, Our World in Data) Average life expectancy at birth of the global population in 2016: 72.0 years Developed countries: 77–90 years (e.g. Switzerland: 83.3 years, 2016) Developing countries: 32–80 years (e.g. Sierra Leone: 53.1 years, 2016) WHO Life Expectancy Population longevities are increasing as life expectancies around the world grow: World Maps of Life Expectancy in 1800, 1950, and 2011 (Source: Max Roser, Our World in Data) South Sudan: 39.21 years in 1981, 56.32 years in 2015 Ethiopia: 43.67 years in 1981, 65.04 years in 2015 Nigeria: 45.63 years in 1981, 52.99 years in 2015 India: 54.29 years in 1981, 68.3 years in 2015 Turkey: 59.3 years in 1981, 75.5 years in 2015 Brazil: 62.26 years in 1981, 75.28 years in 2015 Mexico: 67.04 years in 1981, 76.93 years in 2015 UK: 73.82 years in 1981, 81.41 years in 2015 USA: 74.12 years in 1981, 79.24 years in 2015 Australia: 74.68 years in 1981, 82.73 years in 2015 Canada: 75.4 years in 1981, 82.21 years in 2015 Spain: 75.64 years in 1981, 82.98 years in 2015 Japan: 76.58 years in 1981, 83.62 years in 2015 See, told you it would be short. Ok, next section. Why is this (aging) even happening to you? This question is asking about some general or fundamental nature of aging — what aging and why does it happen? Why has aging — a characteristic that to an organism — been maintained in natural selection? Aging has posed an evolutionary paradox: if natural selection leads to organisms that are for survival and reproductive success, then why or how could evolution favor a process that increases mortality and decreases reproductive capacity? How could genes that cause aging evolve? Does aging have an evolutionary advantage? Evolutionary disadvantage? is seems so detrimental optimal Theories that attempt to answer why aging occurs from an evolutionary perspective are known as theories. evolutionary Focusing on the group, not the individual Efforts to understand why we age go back for centuries. Early attempts suggested that both aging and death are beneficial for humans because they gave new organisms a chance to play and test which variants are more suited for survival and reproduction, i.e. they make room for the next generation. In other words, sacrifice the individual for the greater good. In 1889, the German biologist August Weismann suggested that natural selection would favor species survival and hence aging and death were programmed — in order to make space and free resources for younger and fitter individuals. This theory doesn’t identify a for aging — it gives the purpose of aging, but doesn’t explain how individuals age. mechanism Many early explanations revolved around and survival of the species. This view was held by biologists until some time in the 20th century. group selection It was later argued, in the 40s and 50s, that long-lived individuals could leave offspring than short-lived individuals so the cost of death of an individual exceeds the benefit to the group. This meant aging most likely did not evolve for the “ ”. more good of the species Weismann later abandoned his theory. New theories said that since it didn’t make sense for natural selection to favor aging and death, aging must have evolved because natural selection becomes “inefficient at maintaining function (and fitness) at old age”. See for details. The Life Extension Revolution: Theories of Aging See for details. The Life Extension Revolution: Theories of Aging MA does not suppose any fundamental cause of aging. In this theory, aging is the result of detrimental mutations. Therefore, if these mutations could be removed or fixed, longevity may be extended. The idea that mutations end up causing adverse effects has been by scientists trying to understand human genetic diseases: “many human diseases have been traced to errors that have occurred in genetic code.” However, the current view is that MA is too simplistic. verified and accepted According to AP theory, aging is the detrimental of selection for survival and reproduction during youth. The current view is that AP is the prevailing theory today for why (in evolution) aging occurs, but it’s not fully well-supported. On one hand, biologists have found many genes that enhance fertility in the young (or carry some other benefits early in life) and associated with aging later in life. But on the other hand, they have found many other aging genes that have no benefit associated with them in early life (or at least none that have been identified). side effect do are In any case, the idea that genetic trade-offs may be the cause of aging is prevalent today. So, what’s missing? Some of the things that evolutionary theories of aging don’t necessarily : explain There are some organisms that die suddenly following reproduction (e.g. salmon, octopus, etc.). And sudden death seems to be an example of programmed death (and not a result of gradual aging that is characterized by the side-effect or trade-off explanations. Scientists have found that manipulating some genes seem to delay aging while not affecting reproduction — this also contradicts the evolutionary theory of aging. These theories don’t explain animals like (some) ants, which have a single reproductive female — their existence provides evidence against trade-offs between longevity and reproduction. Evolutionary theories seem to imply all organisms age so they don’t explain organisms that appear not to age (earlier list). There are animals (Painted turtles) where older females (compared to younger females) had reproductive output offspring quality maintaining survivorship. increased and while , which is programmed cell death is responsible for killing cancerous cells, infected cells, and other cells that are problematic during development. Now, this is beneficial (but a problem is it seems to increase later in life) so it hints that senescence may have arisen because of an evolutionary advantage, and not because of some side effects. Apoptosis In conclusion, evolutionary theories provided a theoretical framework that explained many observations, but 1) they don’t offer a complete picture and 2) they don’t offer a mechanistic picture of aging — how do we age? The good news is that we don’t (yet) need to know the complete “why” to try to push back aging and age-related diseases. And that’s because we know a lot about the “how”, about the of aging and how to intervene — that’s the next section. evolutionary mechanisms How is all this happening — what’s making you age? In this section, I’ll quickly talk about the biological basis of aging — the mechanisms, factors, and processes that are making you age. [ ] I strongly suggest you read The Life Extension Revolution: Theories of Aging for details. All aging starts with genetics. Aging is correlated with changes in a variety of biochemical and physiological processes in the body. Determining cause and effect is hard in aging — is A causing or contributing to aging or is A an effect of aging? Scientists examine these processes in a variety of animal models and propose theories to explain the that aging. These, we hope, in turn help us push back aging in humans and hence extend life. mechanisms contribute to may The theories that attempt to explain the mechanisms of aging are generally categorized as follows: theories and theories. programmed damage-related Programmed theories (read here) Programmed theories say that we are to age and die — both aging and death are genetically predetermined and programmed — and the body follows a biological timeline. “Programmed” does not mean evolutionarily programmed; it only means that aging is predetermined by set of instructions. This “programming” may be controlled via different clocks: molecular, genetic, neurological or hormonal or through the hypothalamus. designed See for details. The Life Extension Revolution: Theories of Aging Damage-related theories we’ll discuss (read here) Damage-related theories say that aging results from an process of damage accumulation, where damage is both by-products of metabolism as well as environmental assault on the body. This process of damage accumulation is throughout your entire life and causes aging. ongoing ongoing eventually See for details. The Life Extension Revolution: Theories of Aging It turns out that aging has both of these — both genetic factors as well as various forms of damage contribute to aging. The difference really is about which factor — programmed or damage — is the predominant one. Many theories are a combination of programmed and damage theories. It is now generally believed that the “accumulation of cellular damage” is the of aging. general cause Hallmarks of Aging A breakthrough paper in 2013 outlined — it defined aging as 9 distinct categories (hallmarks) and explained how these processes interact with each other. The paper discussed aging through the lens of damage theory. Hallmarks of Aging The 9 hallmarks can be into 3 categories. grouped are considered to be the primary causes of cellular damage. The first four (Genomic instability, Telomere attrition, Epigenetic alterations, Loss of proteostasis) are considered to be part of antagonistic responses to the damage. These may initially be beneficial and mitigate damage, but eventually they become a problem themselves. The next three (Deregulated nutrient-sensing, Mitochondrial Dysfunction, Cellular senescence) are the end result of the previous two categories of hallmarks and they are responsible for the functional decline associated with aging. The last two (Stem cell exhaustion, Altered intercellular communication) I talk about these hallmarks in a separate blog [ — there will be more in Part 3, when I talk about approaches. The Life Extension Revolution: Theories of Aging ] For us laypeople, here’s a crude visual summary of the hallmarks of aging. Source These 9 hallmarks are determined mainly by genetics, but are affected by environmental factors. And all of them contribute to damage and over time our bodies can’t repair this damage, which eventually leads to aging, age-related diseases, and death — The Self-Destruction Countdown and then The Ultimate Cliff. Aubrey de Grey and SENS A massive figure in the field of rejuvenation is Aubrey de Grey — he’s a world famous gerontologist. But more importantly, he’s been fighting this fight for a few decades — before most people cared about it and before people wanted to put money in this field. When Aubrey’s mother died, she left him with $16 million. He could’ve done anything with the money, but he dedicated $13 million to attack and eradicate aging. He thinks this is one of the biggest problems facing humanity and he’s been working relentlessly to fight it. He describes aging as follows: Metabolism causes damage and damage eventually causes pathology. He , “ says Metabolism (the hugely messy network of homeostatic processes that keep us alive) causes pathology (the hugely messy network of anti-homeostatic processes that kill us).” : Source “Metabolism causes pathology” Therefore, his approach to solving aging is via . maintenance and repair : Source “Metabolism causes pathology” He uses the analogy of a 50- year-old car that still runs well due to exceptional maintenance to make his point. This maintenance approach, he says, should extend the human life span if we keep damage at manageable levels throughout the human body. In summary, “accumulation of cellular damage” is the of aging. general cause Over decades, many attempts have been made to understand aging and researchers made tremendous progress. In fact, recent research suggests that there may be , giving scientists hope that it may be possible to develop approaches and strategies that could help humans live longer and healthier lives. have a limited number of these mechanisms Can’t anyone stop this? : scientists think they can_*_. Good news ( *Not all scientists agree, but still. For the first time in human history, there are (many) scientists who believe we may be able to change how future humans think of and experience life — a new paradigm could result — one that will challenge and change the generally accepted human life limitations.) scientists have already extended life span in other species. Scientists have the lifespan of nematode worms (through genetic engineering) and yeast (through genetic engineering and caloric restriction) by 10-fold. They have also extended life span in mice by over 30%. More good news: increased But preventing (or eliminating) aging is hard and complicated. It’s not going be easy and it’s not going to be quick, especially if there is no societal, political or financial support — which is why need to find ways to get support. in humans we Even though solving aging is hard, scientists are already pursuing some exciting and promising approaches. Even more good news: High level approaches — as of now Below are some of the (high level) approaches scientists are taking in order to extend the maximum human lifespan . They hope to reduce damage and slow down aging by doing the following (in part 3, I’ll talk in detail about what different approaches mean, how they work, and who is doing what in this field): The idea is to build a of human genome sequences, including data from supercentenarians. This would help us 1) understand what makes a life long and healthy, 2) catch illnesses early, and 3) identify risk factors for diseases later in life. Those working on life extension can then use this database. This will play a big role in AI applications for life extension and anti-aging. [Note: There are some very exciting efforts in this space from big tech companies as well as newer startups (and I’ll talk about them in detail in Part 3): IBM Watson, Google’s Calico and Deepmind Health, Chan-Zuckerberg initiative, Intel health and science, IBM Watson, Microsoft Health, Allen Brain Atlas, , , , , and more] Collecting and analyzing data: massive database Insilico Medicine Deep Genomics Turbine.ai AiCure : Currently, a number of drugs that are intended to slow aging are being studied in animal models. (See database). For example, calorie restriction (CR) has been shown to extend lifespan so there are attempts to develop drugs that will mimic this process. Several drugs that are already approved for other uses have been studied for possible longevity effects because they might be mimicking CR effect — these drugs are , , , and . Other drugs have taken different paths, for example enhancement of telomerase activity (see below). Anti-aging drugs Geroprotectors rapamycin metformin MitoQ resveratrol pterostilbene Tissue engineering combines ideas from engineering and life sciences — the idea is to periodically replace damaged tissues or to build biological structures that restore, repair or even replace tissue parts (or even whole tissues), such as bone, cartilage, bladder, muscles, etc. Tissues and whole organs involve specific mechanical and structural properties to function properly. The goal is to engineer tissues with these properties to restore or improve tissue function or entire organ function. This term is sometimes used synonymously with , but regenerative medicine focuses more on the use of to produce tissues. Tissue engineering : regenerative medicine stem cells Stem cells are cells that can be made to grow into other types of cells. In , new cells can be grown to treat a variety of problems: use a patient’s own stem cells to grow organs (such as kidneys) in a lab and replace the patient’s existing failing organs, grow new nerve cells to treat diseases like Alzheimer’s, etc. So, how can stem cells treat so many conditions? A is because “the root cause of most of these conditions is either lack of stem cells or the ones you have left aren’t working properly.” Stem cells : regenerative medicine high level answer : Diseases and conditions where stem cell treatment is being investigated. Source As noted earlier, aging is the accumulation (over time) of damage to cells, tissues and organs. If any of that damage can be repaired, the result is rejuvenation. (Gerontologist Aubrey de Grey’s studies how to reverse the damage caused by aging). Rejuvenation therapies : Strategies for Engineered Negligible Senescence (SENS) There is something called the : a normal human fetal cell will divide between 50–70 times before experiencing senescence — it will not divide past this point.) are specialized DNA sequences at the end of chromosomes and they serve as a protective cap. They shorten at each cell division and when telomeres become too short, the cells senesce and die, i.e. cells stop dividing. Telomeres place a limit on how many times a cell can divide and during each cell division, telomere shorten. And as long as cells have enough of the enzyme telomerase, they keep the telomeres long(er). The problem is that with time, telomerase levels decrease. The idea is to slow aging by reversing the shortening of telomeres — by activating telomerase. It may be possible to remove the Hayflick limit and hence make individual cells “immortal”. Enhancement of telomerase activity: Hayflick limit Telomeres The idea is to introduce beneficial genes or modify genes in the cells — these genes that are delivered in a patient’s cells act as a drug to treat disease and hopefully repair the damage that occurs with aging. FDA has already approved several such therapies. For example, take a field mouse, whose lifespan in the wild is 6–8 months — it’ll get eaten by then. Now, if you put a mouse in a lab, where there are no predators, then the mouse has double the lifespan — it lives 12–18 months. But if you put a mouse on calorie restriction, then the lifespan is doubled to 26–30 months! Now, here’s the magic — enter gene therapy — if you change in the mouse (FGF21 — which humans also have), then the mouse lives 60 months — that’s without changing diet or exercise or anything else except just one gene. Imagine the possibilities! Gene therapy : one gene Source Repairing the 9 hallmarks of aging Remember the 9 hallmarks listed above? Here’s the of some of the approaches to fix the 9 hallmarks — it’s maintained by (Part 3 will have details): roadmap Lifespan.io : Therapies and technologies Source See for a summary of approaches. The Life Extension Revolution: Theories of Aging Aubrey de Grey and SENS Aubrey de Grey believes rejuvenation via is the idle approach — not the other two traditional approaches. maintenance Paradigms for intervention For each damage type, his organization — SENS — has suggested an approach to attack it (more on this in Part 3). These were some high level approaches being tried right now. Next are some high level approaches we hope to see in the future. High level approaches — down the road (a nanometer is one-billionth of a meter): This is at the intersection of nanotechnology, biology, and medicine. The idea is to manufacture and program nano-molecular machines or robots that can enter cells and repair damage, giving us far more control than other approaches. This approach holds one of the greatest promise for curing disease and extending health span. K. Eric Drexler, one of the founders of nanotechnology, hypothesized such cell repair machines and Ray Kurzweil that that advanced medical nanorobotics could completely remedy the effects of aging by 2030. , the accelerating pace of technology is already has already had massive impact. For example, “it took us 15 years to sequence HIV; we sequenced SARS in 31 days,” he said during a 2005 interview, referring to efforts to sequence the genomes of HIV in the 1980s and ’90s and of SARS (Severe Acute Respiratory Syndrome) in 2003. Nanomedicine / Nanobiotechnology said According to Kurzweil : Some people suggest that cloning and stem cell research could provide a way to generate cells, body parts, or even bodies. The US Department of Defense runs a program to research the possibility of growing human body parts on mice. Cloning and body part replacement entire : The idea is to preserve a human corpse, with the hope that reviving it might be possible in the future. More on this in Part 2 (Death) and Part 3 (Approaches) Cryonics : The idea is to replace biological organs with mechanical ones could extend life. More on this in Part 2 (Death) and Part 3 (Approaches) Cyborgs : The idea is scan the mental state(s) of an individual and copying it to a computer. More on this in Part 2 (Death) and Part 3 (Approaches) Mind uploading Here’s a summary of high level approaches to eradicating aging: The takeaways There is no magic bullet that will cure aging. Eliminating aging and extending lifespan will require a . For example, geroscientists can kill off senescent cells, but we need fresh new stem cells to replace the lost ones. In the meantime, medications can help correct our declining metabolism and improve our declining DNA repair processes. wide variety of different therapies Most approaches, as of now, are either in early research or have only been tested on mice — not on humans. In other words, there are no guarantees on how they will work on humans, but to find out, researchers need to perform human clinical trials. According to , “For a drug that targets a single, specific disease, it currently takes about 17 years from discovery in the lab to completion of clinical trials. It takes eight more years for physicians to adopt the drug, making it available to people who need it. That’s 25 years in all. The cost: $500 million to $1 billion, on average. Over the past three years, the Geroscience Network has brought together leading aging researchers from 18 aging centers and academic groups in the United States to design the strategic infrastructure needed to dramatically cut the time and cost required to gain regulatory approval for a new class of drugs that tackle fundamental aging processes.” American Federation for Aging Research This is why awareness and funding is needed — existing infrastructure takes too long to bring drugs to the market. more All of us need to help — “No problem can stand the assault of sustained thinking.” Voltaire Extending life is not crazy. Buying more time is not crazy. A short story: It is December 31, 2017. My friends and I are having a new years eve gathering. At midnight, I go around the room and ask everyone what they want in life (that they can work towards in 2018) — the answers vary — wealth, health, success, love, happiness, peace, travel / adventure, and nothing. After each answer, there’s a note of encouragement — some sort of a cheer — some sign of good wishes. My turn is last, and I say “time” or “more time”. This time the reaction is different, it ranges from chuckle to laughter to dismissal. “Come on, give another answer”, “That’s not a real thing”, “There must be something else you want more”, etc. etc. etc. even They knew what I meant by “time” — I meant time, as in more time than my finite life provided — I wanted the to live longer (and live well, of course). I wanted more years, more days, more hours, more minutes added to my life (and to the lives of people I love). I don’t want to age, say goodbye and leave the world in my 70s, 80s, 90s, or 100s. Equally importantly, I don’t want my loved ones to go — I can’t imagine the loss. But , I want humankind to have an option, an option to get more time, should they want more time. An option to keep staying healthy and living longer. An option to say no to aging and suffering. (And an option to not die — but that’s part 2). very short option most importantly That night, I realized that most people have aging as an and death as an of that process. They’ve accepted The Self-Destructing Time Bomb and The Ultimate Cliff (or they are avoiding thinking about it). And this acceptance is what’s keeping people from seriously and carefully thinking about aging and life extension. accepted inevitable process inevitable result It is important to eradicate aging Most of us are searching for meaning in our lives. I think we do our lives — contributing to the world, having relationships with people, loving other people, being creative, thinking originally, understanding what’s around us and how things work, understanding ourselves, striving to improve ourselves — is what gives meaning to our lives. And the time we get to do all this and more, is not nearly enough. what with And no healthy and happy, satisfied person wants to die . Research shows that people want more time; they want to live their average life expectancy. today longer than When people were asked what they thought was the ideal length of life, 86% said 79 or older: 69% said between 79–100 years of age — the most interesting part is that life expectancy at the time was 78.7 years — this means most people wanted to live their life expectancy. In fact when they were asked about their ideal life span, they said around 90 years (= median ideal life span), this was 11 years than the average U.S. life expectancy then (2013). longer than longer — The median ideal life span is 90 years — about , which is 78.7 years Source 11 years longer than the current average U.S. life expectancy Looks like people want to live longer than what is given to them. The problem is that we age and we deteriorate. And this robs us of a good quality of life. That why it is important to attack and eradicate aging — doing so would both improve people’s healthspan extend lifespan. In doing so, humankind will have to live healthier and longer lives. is and an option Life extension is just the natural progression of existing medical practices — we would go from curing diseases (and the side effects of aging) to preventing them. This is the goal: The goal is to not live a really really long time as an old person, it’s to stop and reverse aging. There’s dedicated effort to overcome disease and aging — a) to eradicate cancer and diseases so people won’t have to worry about them in their 60s and 70s, b) to overcome frailty so people won’t have to worry about it in their 80s, 90s, and beyond, and c) to eliminate aging so people won’t have suffer from age-related diseases. ever And once we succeed, future generations will look back and wonder why didn’t do this sooner. Why now The current technological (and biotechnological) revolution could make us the first generation of humans with a life expectancy of over 1000 years. We standing on the brink of a revolution — one that will slow down aging, then eradicate it. There’s a massively profound transformation coming our way in the next 10 or 20 years. are You might be wondering that some subset of humans have always wanted this, so what’s so different now? Major investments and efforts are now starting to be made in this field — more in part 3. [I’m working on compiling approaches and visually representing a “map” of approaches. It’s taking much longer than I had anticipated. When it’s done, I’ll add a link with details.] Technologies and tools we have now are improving exponentially: genomic sequencing, gene editing, big data management, artificial intelligence, simulation and actual models (of animals and non-animals) are all getting better day by day. Health and medicine have now merged with technology — this wasn’t always the case. For example, after the genome project, we can now reprogram biology and life — something we couldn’t do before. So much is now known about the pathways, genes, proteins, processes that contribute to aging. A lot of people are now trying a variety of approaches (aided by the technologies and tools listed above) to interfere with these contributing factors, and translating the research to clinical trials of drugs and therapies to extend lifespan is imminent. Genetic therapies have increased mice lifespan, allowing them to live about 30% longer. Imagine living 30% longer — we’d be living up to 105 — ! Recent stem cell therapy application has doubled life expectancy in a particular type of mouse. Imagine doubling our life expectancy — we’d be living up to 160! on average The purpose of these drugs and therapies is to put an end to aging and its terrible consequences — deterioration, dysfunction, disease, and subsequent death. The idea is to get a few extra decades, during which we’d have new ways to attack this problem, and hence get few (or more) extra decades and so on. One last thing Before we stop, let’s go one step further. Does eradicating aging allow to live healthy lives for as long as they want? No, not yet. First: even if in the next 20 years we have therapies that allow us to live for a few decades more, then would they really help people in their 70s, 80s, 90s and beyond? Unless we can reverse aging by then, these therapies may not buy them more time. Second: even if we eradicate aging, we can still die from other events. The option to live long isn’t really an option in these two scenarios. People and probably die in these scenarios. everyone can will Eradicating aging isn’t to truly give humankind an option to live longer or an option to not die. But eradicating aging is still a problem to solve. sufficient necessary I think we would all agree that death of someone close to us, independent of the cause, is heartbreaking at a personal level. Furthermore, the cost to humanity of individual deaths is equally heartbreaking, even though it is something we rarely think about. Each individual has tremendous knowledge, insight, life experience, and loving relationships. All of those are gone when an individual is gone. So, eradicating aging is step 1. Step 2 is seriously thinking about death and finding a way to control it. That’s Part 2 — Coming soon-ish. Notes Note 1: It is possible (and very likely) that I missed some very important points or got some things plain wrong. If you find errors, then please let me know (especially about theories of aging and approaches to life extension). I’ll update the blog. Note 2: This blog is Part 1 of a 3 part series. Part 1 is about aging, Part 2 will be about death, and Part 3 will be a deep dive into approaches to eliminate aging and death. Note 3: This blog is structured as follows: what happens to you as you age, do all species age, why do you age, how do you age, how can aging be attacked, and why it’s important to attack aging.