Date posted: 09.12.2013
Aging: philosophy and reality
What is aging?
There are literally dozens of answers to that question, even if we restrict ourselves to purely academic views. In the days when I was the executive director of the American Aging Association, there were – or so it seemed – as many aging hypotheses as we had members of the association. Almost all of the ideas, however, had a few problems. For one thing, each hypothesis tended to explain only a limited area of observation, such as a select body of data (just somatic cells) or a narrow part of the biological world (just mammals), rather than being in any sense universal.
Many “theories of aging” excluded tortoises, hydra, plants, nematodes, lice, seaweed, mammalian fertilization, germ cell lines, clones, or anything else of real interest. In fact, many “theories” exclude everything except human aging, and usually not all of that. Too bad: looking at the exceptional and the broadest biological sample are how you get the most scientific insight. Some species, for example, never age in the first place, which many “theories of aging” ignore completely. The second problem was that most theories were actually inconsistent with the available data, particularly when you looked at the details. Wear-and-tear theories, for example, don’t explain the immortality of the germ cell line. The most damning problem however, was that most aging “theories” simply weren’t testable: they were interesting ideas, but you could neither prove nor disprove these ideas.
In short, they weren’t theories at all.
A theory must be comprehensive, accurate, and testable. Even now, most “aging theories” are still merely observations or intuitive guesses about a narrow segment of our world. For example, some people believed that any animal had a limited number of heartbeats and that this figure somehow underlay all of aging. The fact that plants and some animals lack hearts and still age was somehow ignored, as was the observation that the facts were actually entirely inconsistent with the data. Heartbeats simply don’t predict aging.
Not that the idea made sense anyway.
Similar problems underlay most other theories, even theories that – for no logical reason whatsoever – seem to have general acceptance among the public. Endocrine (and similarly the “vital substance”) theories of aging, for example, assume that the aging clock for your entire body lies in some set of endocrine glands, but if endocrine glands time aging in the rest of your body, then what times aging in the endocrine glands? And how do we explain aging in cells? How about animals or plants that lack the candidate endocrine glands in the first place? Of course, the data shows that endocrine replacement may or may not have benefits, but has no effect whatsoever on aging. So much for endocrines. The idea was premised on correlational observations, which would be like saying that since gray hair correlates with aging, we need only dye your hair and you’ll be young again.
Well, perhaps not.
Various wear-and-tear theories are no better, even if they suit our intuitions about entropy and how our cars, houses, and cell phones “age” over time. Actually, however, living things simply don’t undergo entropy the same way at all. There are a number of idea that are central to the idea of wear-and-tear – free radicals, mitochondria, cross-linking, lipofuscin, DNA damage, waste product accumulation, and others – but none of these remain credible explanations when arrayed against the data. For example, germ cells don’t age and cell aging can be reliably reset at the time of fertilization. So much for the universal nature of wear-and-tear as an explanation for biological aging. If cells merely undergo wear-and-tear and then fall apart with time, then why don’t these cells fall apart and why can we reverse the entire process quite reliably?
There is an entire group of evolutionary theories – the disposable soma, group selection, antagonistic pleiotropy, and others – that are reasonable enough if all we want is an evolutionary explanation. These provide teleology, but don’t explain the underlying biological processes that are occurring in the organism as it ages (or doesn’t). But when we ask these theories to explain the actual pathology of aging, they point vaguely at wear-and-tear theories and shrug. Good evolutionary science perhaps, but they miss the point. We would like to know exactly what does happen as we age, not why it should happen.
While these notions fail to explain the available data – including the fact that fertilization resets cell aging, for example – the more daunting issue is that most of these explanations are not theories at all, but merely loosely-stated hypotheses.
The critical element to ANY scientific theory is that is must be disprovable.
I could tell you that “invisible and unknowable forces cause aging”, but if they are invisible and unknowable, then they can’t be proven or disproven. This is a faith, not science and certainly not an explanation of aging. I have every respect for faith, but faith isn’t science and faith doesn’t help me provide clinical therapy or offer a viable explanation for how to improve medical care when you get sick.
A good theory makes a testable hypothesis.
At the moment, there is only one theory of aging that meets our three criteria of being comprehensive, consistent with the known data, and testable. That theory – the so-called telomere theory of aging – is, unfortunately, rarely spelled out in detail and almost universally misunderstood in the first place. For example, many people assume that this theory suggests that aging is determined by telomere length, while in reality it suggests that aging is determined by a changes in telomere length.
The telomere theory of aging has so far been tested in cells and tissues and in both cases the results were consistent with the theory: when you reset telomere lengths, you reset aging, whether in humans or in animals, in cells or in tissues. The theory has also been tried in vivo, using an oral compound, and the initial results likewise support the theory. These various experiments underline the importance practical interventions over simplistic explanations: if you can’t change it, you can’t prove it. Science demands that a theory be testable; the medical viewpoint demands that a theory offer a potential intervention. If you can’t test it, then it isn’t science; if you can’t intervene, then it isn’t medicine.
At Double Helix, our intent is to test a theory, but far more importantly – to us and to everyone else – our intent is to offer interventions.
Date posted: 22.11.2013
Extending Life, Not Misery
Most of us assume that aging equals illness.
To be honest about it, we don’t usually put it that bluntly and we often deny it, even to ourselves, and yet we tend to assume that unless we are struck down suddenly – an unexpected automobile accident, a sudden pneumonia, a fatal heart attack – we will gradually lose the ability to care for ourselves, lose the ability to live in our own homes, and lose the ability to enjoy our lives. Are we wrong?
What if we could cure age-related disease?
What if we could be older, true, but be as healthy as the average young adult? The assumption – aging equals illness – shows itself in how we respond to the question “Do you want to live to be 120?” Most of us don’t. The Pew Foundation, and then the Canadian Association of Retired Persons, asked this exact question. The majority of us said we wouldn’t want to live that long, even if people had access to “medical treatments that slow the aging process and allow them to live decades longer”.
But look carefully at what the question implies.
Most of us – having close friends and relatives with Alzheimer’s disease or who live in a nursing home – immediately translate the question from “do you want to live to be 120” into “would you be willing to live in a nursing home, unable to care for yourself, for another 30-40 years?” We make this translation unconsciously, but quite naturally: after all, that’s what it means to be that old, doesn’t it? When look at the question with this assumption in our minds, why would we want to live to be 120? Not surprisingly, most of us wouldn’t. Why would you – or anyone – want to be kept alive even longer, unable to feed yourself, unable to recognize your own children, and unable to enjoy life around you? Not surprisingly, most of us would prefer an easier fate, a sudden illness for example, rather than submitting to decades of nursing care.
But let’s change our question a bit.
Instead of “do you want to live to be 120 (in a nursing home)?”, let’s ask about a different outcome. Imagine that we could prevent Alzheimer’s disease, prevent heart disease, prevent osteoarthritis and all the “…the thousand natural shocks that flesh is heir to”. Imagine that you could have the health and function of a 30 or 40 year old. What if we could “turn back the clock” and prevent age-related disease? If you could have the health of a much younger person – even at 120 – what would you do then? Look at the question now, with different assumptions. The question becomes more interesting: “Do you want to live to be 120 if you could have the health of a young person?” It’s such an odd, such an unbelievable (beyond the pale?) question that most of us discount it immediately, and yet…
And yet perhaps it’s not so odd a question after all. As it turns out, a great deal of research shows that we may soon do exactly that. We can now reverse aging in human cells and in human tissues in the laboratory and at least one Canadian biotech firm is about to take the same approach in curing age-related diseases. They may well change everything you think you know about aging and disease. Older yes, but why not healthier as well?
The original question assumed a tragic end. At a very real level, the Pew Foundation was asking us if we wanted to be unhealthy for a longer time. A better question is whether or not we want to be healthy for a long time. It’s a much better question, particularly in light of what is about to happen to our ability to cure age-related disease.
Or try an even better version of the question.
If you had only two choices, would you rather suddenly become 30 years old or suddenly become 90 years old? Would you like to have the health of the average 30 year-old or would you want the health (and the health problems) of the average 90 year-old? What if you could live to be 120, not by living longer in a nursing home, but by being healthy, living in your own home, and being free to enjoy an active life? But is this realistic?
It is if we can cure age-related disease, and we may soon do precisely that.
Some of us discount the question for other reasons, feeling it would be wrong to “grasp after youth”, yet we chose health every day, with nary a pause for thought. We even chose the mere appearance of health, even when it does nothing to improve our health. It’s not surprising that we should take antibiotics for pneumonia and replace our aging knee joints when osteoarthritis prevents our walking without pain, but we also dye our hair and pay a truly astonishing amount for Botox, when neither of these provides anything but an illusion.
Soon, however, we will be able to prevent and cure Alzheimer’s disease and regrow our own natural knee joints, so that they work as well as they did when we were young adults Would you want to play tennis at age 90 if your knees and your heart were healthy?
Until now, when it came to aging, the medical community has also tended to “answer the wrong question”. We still think of aging as inevitable and age-related disease as incurable. But the outcome is that we often discount disease in our elderly patients, treating them often as not only incurable, but invisible. Few of us would be callous enough to ignore the suffering of children, yet some of us have quietly ignored suffering in the elderly, perhaps not because we don’t care, but because we feel impotent in the face what we thought of as inevitable disease.
Research now shows that this view is naïve. Aging is not inevitable nor is age-related disease incurable. We need to take the results we have in cells and animal studies and go further: we need to eradicate the diseases of aging. Suffering is not inevitable, nor can we afford to ignore the elderly. Over the past century, we worked hard – and worked together – to cure polio and other common diseases of the young. Compassion for the young is common; an equal compassion for the old should be no less equally common. It is time to find out what compassion and hard work can accomplish.
It is time to save both our health and our lives.
Date posted: 12.11.2013
Telomerase and Cancer
Telomerase does not cause cancer.
The statement is accurate, but it’s not that simple nor is it a naïve concern.
Telomerase and cancer are clearly linked – telomerase has been called “the two-edged sword” with aging being one edge and cancer the other – and the question thus deserves a more complete and more sophisticated answer. As always, discussions that involve causation tend to miss the point, resulting in misconceptions and errors. Instead of asking about causation, consider a few questions that are far more practical and clinically useful:
- If we increase telomerase in somatic cells, would the incidence of cancer rise in an average group of healthy patients?
- If a patient already has cancer and we increase telomerase in their somatic cells, would that patient get better or worse?
- If we have a population of healthy patients and we wish to decrease the overall incidence of cancer, would it be better to increase or decrease telomerase activity?
These sort of questions are much closer to the nub of what we actually want to know, as they constitute useful clinical information, information that is useful to both the physician and the average patient. Putting it bluntly, if I want to be healthy, do I want telomerase or not? To answer just as bluntly, you generally want more telomerase rather than less, or to put it more accurately, you generally want longer telomeres rather than shorter telomeres.
The reason the answer is “generally” true is that elongating your telomeres – like almost every function in biology and every therapy in medicine – has both an upside and a downside. The upside is that longer telomeres stabilize your genome, and hence lower the probability of cancer. The downside is that – once you have a cancerous cell – cancer needs to maintain telomeres just to survive. In other words, long telomeres prevent cancer, but cancers require telomeres or they may spontaneously go into remission.
There is a balance of risk. If you don’t have cancer, you definitely want long telomeres. If you already have cancer, you would prefer it if the telomeres in your cancer cells would continue shortening and kill the cancer cell before the cancer cell kills the rest of you.
Consider why this balance occurs. In normal cells, the repair and recycling of cellular elements – in this case we can focus on DNA repair – depend on changes in telomere length: as telomeres shorten, DNA repair slows down. In the young cell, DNA maintenance is stunningly accurate and efficient. In the aging cell, DNA maintenance has become slipshod, showing decreasing accuracy and efficiency. In old cells, the genome is no longer defended as competently and the outcome is an increasing number of mutations and errors, leading to cancer. To put it simply, the longer your telomeres, the more stable your genome. As telomeres shorten, genomic stability falls and cancer incidence rises.
On the other hand, once a cell’s genome has accrued enough errors to become cancerous, there are still three internal cellular obstacles: DNA repair, the cell-cycle braking system, and telomere loss. If DNA repair fails (which occurs as the telomere shortens), then cell division is generally halted as the cell detects DNA errors. However, as the telomere shortens, the cell also becomes sloppier in applying the “brakes”: the aging cell is more prone to continue dividing even in the face of DNA damage that would halt a younger cell. This leaves the telomere as a final defense. In normal aging cells, shortened telomeres result in a failure to divide (or to put it more accurately: a slower rate of division, a decreased likelihood of continued division, and an increased likelihood of apoptosis or even necrosis). If the cancer cell no longer divides, then it isn’t a clinical problem. If it can’t grow, it can’t kill you. Unfortunately, there are a number of ways that cancer cells elude the problem of telomere loss, at least for a while, and almost all of them involve maintaining telomere length. Not surprisingly, telomerase is expressed in about 85% of human cancers and telomerase inhibitors are seen as potential cancer therapies. If we have cancer cells, then we would prefer it if their telomeres would be entirely lost, resulting in dead cancer cells. If you already have cancer and we re-extend your telomeres, that wouldn’t cause cancer, but it might increase the ability of your cancer to survive and metastasize.
In short, telomere extension might increase mortality in patients with a pre-existing cancer, but if patients don’t already have cancer, then telomere extension would prevent cancer from occurring in the first place. Neither telomerase nor long telomeres cause cancer, but either telomerase or long telomeres could permit cancer to grow once it gets a foothold.
To return to our practical questions, let’s construct some evidence-based, rational clinical advice for a hypothetical patient population. If a patient comes to us with a known prostate cancer, we would probably recommend against a telomerase therapy. This recommendation is not because telomerase causes cancer, but because telomerase therapy might increase the likelihood that the cancer would continue to grow and would metastasize. On the other hand, if a patient comes to us with no known cancer, we would recommend telomerase therapy to prevent getting cancer in the first place.
This is not a new therapeutic dilemma: it’s actually true of a great many other clinical options. Consider exercise: does it cause heart attacks or is exercise good for you? Most of us – both physicians and the general public – are in favor of exercise as a preventative action: patients who exercise are considered to be less likely to get a heart attack, for example. On the other hand, if a patient has just had a heart attack this morning, we certainly don’t recommend that they run a marathon this afternoon. Does exercise “cause” heart attacks or does it prevent heart attacks? Exercise doesn’t actually cause heart attacks, but it can contribute to them or trigger them if you already have enough atherosclerotic disease. Most of us, however, think of exercise as healthy, and with good reason.
Overall, telomerase therapy is – like exercise and with similar caveats – a beneficial clinical intervention, but one that must be discussed in context.
Date posted: 28.10.2013
The Status of Aging Diseases
As of 2013, we can neither cure nor prevent a single age-related disease.
Even at our absolute best – and then only questionably and in one or two cases – can we even slow the unrelenting progress of any of our myriad age-related diseases. Trying for an optimistic view of current medical interventions, and even if we restrict our claims only to treating symptoms, we can offer only partial interventions at our best. Medical science offers a great deal – preventing and treating infections, safer surgery, better obstetrics, better therapies for diabetes to name only a handful of minor miracles – but we can do essentially nothing for age-related diseases To be fair, we often know very little of how these diseases work and perhaps far too much about their symptoms. Given what we do know, it’s easier to treat what we can understand – the symptoms – and what we know how to deal with, if only somewhat. Even our symptomatic interventions fall far short of what budgets and compassion demand of us: the costs are too high, the benefits too small.
Consider osteoporosis, a relatively simple age-related disease. We pretend we understand the pathology of the aging joint, but we do so with a wave of our hands – “the joint wears out, what can you expect?” – while we avert our eyes from any deeper understanding and walk past our own ignorance. If a joint wears out, WHY does it wear out when it does? Why in some people and not others? Why in some species and not others? Why in some joints and not others? Our treatments are better: we remove the old joint and we substitute an artificial joint. It isn’t perfect and certainly not as good as a young, healthy joint, nor does it last as long as a young, healthy joint, yet it is all we have – for now – and we try. But the average cost of an artificial joint approximates forty thousand dollars, requires surgery, surgical risk, painful recovery, and acceptance of what is only a partial solution.
Aging vessels – coronary artery disease, angina, heart attacks, strokes, congestive heart failure – are worse. While joints “just wear out”, our model of vessel disease is more complex, yet still frighteningly incomplete. We point the finger of blame at cholesterol, smoking, hypertension, and diabetes, not because these factors cause aging vessel disease, but because they are known to be correlated with these problems of our arteries as we age. Some children, those with Hutchinson-Gilford progeria, have atherosclerosis while having none of the “classic” risk factors; some adults have all of these risk factors, yet no evidence of atherosclerosis. Why? Not because our understanding of the pathology is wrong, but because our understanding is incomplete. Our treatments are equally incomplete and insufficient. At the extreme end, we can transplant vessels (or even hearts!), yet the outcome is not complete health – young vessels, or a young heart – only a temporarily better hold on a tenuous life. Yet what else can we offer? Quite a bit, actually, though still not a cure. We offer statins, anti-hypertensive medications, and a plethora of other drugs for the risk factors we hope we understand. We use drugs, trying to control the risk factors, such as diabetes, cholesterol, or blood pressure, but the outcome is still compounded of expense, side effects, and only a minimal improvement of our risks.
Alzheimer’s disease is worst: we have nothing to offer beyond a simple compassion. We cannot even offer hope: the average lifespan after the initial diagnosis of Alzheimer’s disease is seven years and we have nothing that is known to halt – or even slow – that inexorable slide as we lose our souls and fall towards our death. Once again, and despite correlations with beta amyloid and tau proteins, we not only don’t know what actually causes (rather than correlates with) the disease, we have no way to treat even those correlations. Every drug trial that has tried to remove or prevent amyloid deposits has failed clinically: we have yet to find a single effective intervention for amyloid, let alone slow Alzheimer’s disease itself. As with other age-related diseases, the outcome is expensive medical care – nursing homes prominent among those costs – but without even partial improvement. Alzheimer’s remains a disease without any treatment.
As we look over the state of care for all age-related diseases, the view is a pessimistic one. All of our treatments are maximally expensive and minimally effective. Why?
Not knowing what to treat, we treat what we can see; not knowing causes, we treat outcomes. But doing so – treating the downstream problems rather than the upstream causes – we find ourselves frustrated and disappointed when we can do so little – and at so high a cost. Could we do more if we understood the “causes” of aging? Perhaps, but the problem is not one of finding the cause of aging, but rather finding the most effective point of intervention. If we could understand the cascading problems that underlie the diseases of aging, where – what one single point perhaps – would be the single most cost-effective point to intervene? Or perhaps we could simply ask, what is the most effective (cost-effective or otherwise) place to cure and prevent the diseases of aging? Clearly, the most effective point to intervene is not vein replacement, statins, artificial knees, beta amyloid, or any of those dozens of random targets we aim at currently. We need a better understanding of aging and a better target for clinical intervention in the diseases of aging.
Aging is a process in which cells change their patterns of gene expression, a process which gradually brings on cell dysfunction, failing tissues, and the clinical diseases that so trouble us as we grow old. The pattern itself changes in response to the gradual loss of telomere segments at the ends of our chromosomes. It is not the length of the telomere itself, but the relative change in length that gradually alters gene expression and that culminates in human disease. While we might move a tiny bit “upstream” and strive to alter the patterns of methylation and acetylation that define those epigenetic changes, we now know that the single most effective point of intervention – not the cause, but the most effective target – is the telomere.
To date, research has shown that we can partially reset aging by using a small-molecule approach: astragalosides show a significant effect on the aging of the immune system, for example. While the results are promising, we are about to move forward with a far more powerful approach – the so-called large-molecule approach – and try to completely reset telomere lengths.
By aiming at the most effective single point of intervention, we will not only cure and prevent age-related disease, but we will prevent the tragedy and waste that result from disease and from aging itself.
Date posted: 15.10.2013
The notion that telomeres play a central role in both age-related disease and aging itself is generally misunderstood and is often criticized without an actual understanding of either disease or telomeres, yet there is a growing sense of the obvious about the role of telomeres in human aging and disease. More and more people – in the street, in the clinic, or in the lab – have the working assumption that telomeres somehow define aging and that the relationship is obvious, which is certainly an overstatement.
We are living through the reality of Schopenhauer’s ironic remark that all truth has three stages: first ridicule, then violent opposition, and finally the belief that it was completely self-evident and it was obvious all along. Nevertheless, even those who assume the importance of telomeres to aging – even those with research or clinical backgrounds – often share one of the many common misconceptions.
Misconception #1: it’s telomere length that matters
The first inaccuracy is that telomere length defines age, which is almost true, but entirely wrong at the same time. The critical measure is not what you have, but what you lost. Putting it more accurately, the length of the telomeres has nothing to do with age, rather it’s the change in telomere length that determines cell aging. The fact that mice have long telomeres is often cited as evidence against telomeres as determining aging in an organism, yet the absolute length is irrelevant. If, however, you watch the change in telomere lengths from birth to senility – in mice as well as other organisms – the correlation is clear and unambiguous. The key to aging is not the telomere length per se, but the way in which a shortening telomere causes changes in gene expression: as the telomere shortens, gene expression changes, DNA repair and molecular recycling (e.g., protein production and breakdown) rates both slow significantly. The result is a gradual increase in the percent of errors in both DNA and biologically critical molecules, for example SOD, elastase, and others. These errors have a profound effect on the cell as a whole, but also undercut mitochondrial function: more free radicals are produced, more escape, fewer are scavenged, and less damage gets repaired when it occurs. Aging occurs not because you have short telomeres, but because your shortening telomeres have caused your cells to stop dealing with the day-to-day damage at an effective rate. For those of you who want a longer discussion and formula describing molecular turnover within aging cells, I refer you to my first book, Reversing Human Aging, but the quick formula is this:
Assume a constant rate of cell damage (here 1%/unit time) and that anabolism equals catabolism (i.e., there is a constant pool size). Then if the percentage of damaged molecules equals and the percentage of molecules produced per unit-time equals M, then the formula defining the accrued damage is:
= 1 + [ (100-M)/100]
if M = 50% in a young cell with a high turnover rate, then = 2% (very little damage)
if M = 2% in an old cell with a low turnover rate, then = 50% (critical damage)
Misconception #2: chromosomes unravel, cells die, and that’s aging
A related inaccuracy is common to almost all the news stories that try to explain telomeres to the general public: “telomeres shorten, the DNA unravels, and the cells die.” Chromosome simply don’t unravel in normal aging. To the contrary, cell aging begins long prior to the telomere’s putative disappearance. Only in the most extreme cases (such as the F5 generation of telomere knockout mice) do cells ever “lose all their telomeres”. It simply doesn’t happen in normal organisms as they age. The most important change, alluded to above, is not that telomeres are lost (or that the chromosome is at risk), but rather that the shortening telomere has caused a changing pattern of gene expression, usually referred to as the telomere position effect (TPE). Not only do a great many genes near the telomeres change expression as the telomeres shorten, but these genes go on to change the expression of more distant genes as well, including critical changes in the master epigenetic regulators, such as histone methyltransferases and DNA methyltransferases. This effect occurs long before growth arrest occurs, long before you “run out of telomeres”, and long before you get “frayed chromosomes”. In real life, your chromosomes are actually in pretty good shape even if you live to be 120 and they only time they actually fray is during decomposition. The result of shortening telomeres is an aging cell, but not because the chromosomes unravel. Not at all. The chromosomes are fine, thank you, but the pattern of expression has changed remarkably and to the detriment of cell function. Cell aging is caused by a “continuous spreading of telomeric heterochromatin” which can cause either a decrease in gene expression or an increase in gene expression, depending on the gene in question One example of this effect occurs in Facioscapulohumeral Muscular Dystrophy (FSHD) where the gene is only 25-50 kb from the telomere, although much more distant effects have been documented as well.
Television personalities notwithstanding, your chromosomes don’t come apart, but your changing pattern of gene expression does result in your body’s “coming apart” as you acquire age-related disease.
Misconception #3: there are “aging genes”
This brings us to a third inaccuracy, quite common to the research world: the idea that “genes cause aging”. Putting it succinctly, there are no aging genes, only aging patterns of gene expression. Aging is not genetic, it’s epigenetic. Just as the difference between your nose and your toe is not a matter of having different genes, but having the same genes with a different pattern of gene expression, so too the difference between your body at age 5 and at age 95 is not different genes, but a different pattern of gene expression. There are no more “aging genes” than there are “nose genes”. It’s quite true that aging and noses are both dependent upon genes, but they are defined by the pattern of how those genes are expressed, not by specific genes for a body part or for aging. You might better say that ALL genes are aging genes: the epigenetic pattern of aging results from changes throughout the chromosomes, not from a few “aging genes”. It’s a gestalt, not a few genes.
The same misconception occurs in regard to age-related diseases. One example is that of Alzheimer’s dementia in which genetic predilections do occur, but even apoE4 is not an “Alzheimer’s gene”: it’s a normal gene, although associated with an increase in the risk of Alzheimer’s as you age, although not always. Also, thinking of Alzheimer’s as a “genetic” disease merely looks at a single, static set of parameters – your genes – and ignores the epigenetic changes that occur dynamically over time. The result is that genome-wide association studies (“GWAS”) identify a great many gene associations with neurodegenerative diseases, but these genes explain only a tiny portion of the risk of actually getting the disease, as occurs in the case of apoE4. Alzheimer’s disease, coronary artery disease, stroke, osteoarthritis and the entire gamut of age-related diseases are not “genetic diseases” but are more appropriately and usefully thought of as “epigenetic diseases”. Only when we recognize the subtle – but critical – difference can we begin to prevent and cure these diseases effectively.
Misconception #4: telomere length(s) predict length of life
This misconception arises not because there isn’t an element (a strong element) of truth in the statement, but because the statement implies several wrong assumptions, so it ends up being not only wrong, but essentially meaningless.
Let’s look at the truth first. To do so, we’ll make several naïve (and usually unrealistic) assumptions:
1) You are only going to die of one particular age-related disease, such as coronary artery disease, and no other disease whatsoever, no matter what you do to yourself.
2) The only predictor of your having a heart attack is the state of your coronary arteries and the only predictor of your coronary disease is the telomere lengths of your vascular endothelial cells (rather than lifelong diet, etc.).
3) Your coronary artery disease is gradual and accumulative – and the rate of shortening is invariant despite any short term changes in diet, exercise, or other risk factors (such as smoking, blood pressure, or cholesterol to name just three risk factors) until some predictable “tipping point” occurs when your endothelial cell telomeres reach a certain precise length and then occlusion inevitably and instantly occurs.
4) Finally, despite the inevitable variation that will be present in those telomere lengths, there is a particular length measurement – whether it’s the shortest telomere or the mean telomere – that is the precise and only predictor of that tipping point.
You see how unrealistic this set of assumptions can be, but if these were all true (i.e., never) then we might reliably predict your actual lifespan based on your telomere lengths. Of course – and perhaps this is the most unrealistic idea of all – we would have to do biopsies of your coronary arteries to measure the important (i.e., predictive) cells that cause disease, something that very few patients (in fact, very few physicians of those patients) are willing to have done to them. Blood sample, yes; coronary biopsies, not me!
The reality is that most of us have multiple age-related diseases in progress in multiple tissues and organs, any of which might finally kill us. Predicting exactly which organ is most likely to kill us is strictly a statistical bet, not a reliable prediction. Even if we knew (how could we?) that you would definitely die of a coronary artery occlusion and not die of any other problem, such events are not merely probabilistic, but they are actually stochastic: they are affected by random events such as small clots or transient inflammation that are not strictly speaking a local problem of the coronary arteries at all. Rather they involve other tissues and organs, as well as transient whole-body events, such as infections. As a result of such stochastic events (and other factors, such as dietary changes, medications, behavioral risks, etc.) the risks do not climb in a gradual curve, but rise and fall in spurts and unpredictable jumps that defy mathematical precision – in fact they defy mathematical imprecision for that matter. Moreover, since there are innumerable cells in your coronary arteries, each with its own set of telomeres, and since each endothelial cell has 23 chromosomes, each with four telomeres, which telomere in which endothelial cell would we use for predicting lifespan? Or do we have to remove every single cell and measure the telomeres? Finally, we can’t actually (at least practically) sample the endothelial cells on real patients in the first place.
Most clinical telomere assays are based on easily available cells, such as oral swabs or white blood cell samples. Such samples may be – quite loosely – correlated with the telomere lengths of your coronary endothelial cells, but the correlation is only fair and nowhere near precise enough to be an accurate predictor of your coronary artery disease, let alone predict your lifespan.
There is one other problem in using serum samples, particularly if we do them serially, in an attempt to see “how things are changing with time”. For example, we might measure the telomere lengths in your lymphocytes, then have you change your lifestyle, then measure them once again in order to show that the intervention has “extended your telomeres”. Unfortunately, such measures don’t show what you might think. Even if your telomeres are several thousand base pairs longer after the intervention, that would not show that your telomeres had actually “gotten longer”. Surprising, by true.
Consider an analogy. Imagine that instead of measuring telomere lengths in lymphocytes, you were to measure the age of inhabitants of one particular city block over time. The first time we interview those living on that block, imagine the area is economically depressed and populated largely by elderly retirees with an average age of 75 years. Now, over a twenty year period, we use a “clinical intervention” and we change the “lifestyle” of the city by offering tax breaks for new start-up companies, repair the old streets, increase the police presence, and so forth. As a result, perhaps more young professionals move into the area and those young people have even younger children, resulting in an average age of only 25 years. Have we “reversed aging” in the population? Not at all. Certainly, the average age has dropped fifty years, but not because we turned back the aging clock in the inhabitants (or even any single one of the inhabitants), but because the old inhabitants died and a new population of younger people have moved into the area.
The same process occurs with regard to circulating white cells in your blood. Even if the “average age” of the white cells (i.e., the average telomere length) has improved, it is not because we have relengthened any particular telomere, but because we are sampling a different and newer population of white cells. In short, serial sampling of peripheral white cells is not as reliable as we wish it were. In real life (i.e., in clinical measurements of peripheral white cell telomeres), it’s not as bad a watching an urban neighborhood over a fifty year period, but the assumption that we can relengthen telomeres in peripheral cells is usually based on wishful thinking rather than on an understanding of white cell population dynamics. We can certainly measure peripheral white cell telomere lengths over time, but interpreting differences in telomere lengths is chancy and should be taken with a grain of salt. It rarely means what researcher would like you to believe it means.
Even is all of this weren’t enough to undermine our faith in the value of telomere lengths as a predictor of lifespan, as I pointed out above, the key issue isn’t telomere length in the first place; the key issue is the change in telomere length. It’s the change in length that changes the pattern of gene expression, that underlies age-related pathology in the first place. In short, I might have much longer telomeres than you do and – even if we could overcome all the other issues discussed in this section – I might still age faster than you do and I many die of any number of age-related diseases long before you reach a comfortable and healthy middle age.
If we wanted to give our best guess as to lifespan (or at least a better correlation), we should be measuring the telomeres from every organ of the body, with an emphasis on those tissues that are most likely to show age-related pathology that results in mortality: coronary vascular endothelial cells, microglial cells of the brain, etc. While any reasonable person, faced with the above problems in using telomere lengths to predict aging and lifespan would probably throw up their hands and surrender, the fact is that even serum-based telomere samples are actually somewhat correlated to lifespan.
Misconception #5: Some aging disease can’t be related to telomeres
Almost invariably, someone – almost always someone without any knowledge of human pathology – will argue that “telomeres couldn’t possibly cause heart disease and Alzheimer’s dementia!” This naïve criticism reflects a number of accurate, but irrelevant facts. In the case of coronary artery disease, the argument goes like this:
1) telomeres only shorten during cell division, so non-dividing cells don’t lose telomere length as you age,
2) cardiomyocytes almost never divide, so their telomeres certainly won’t shorten as you age, and
3) so heart attacks can’t possibly be due to telomere shortening!
In the case of heart disease, the summary of this criticism would be as follows:
- Telomere loss can’t cause heart attacks because heart muscle cells don’t lose telomeres.
Unfortunately, this is almost exactly like saying:
- Cholesterol can’t cause heart attacks because heart muscle cells don’t accumulate cholesterol.
Both statements are not only foolish and misleading; both statements are also wrong. It’s not the heart muscle cells that underlie the pathology, it’s the coronary arteries, which DO lose telomeres and DO accumulate cholesterol. The fact that cardiomyocytes don’t divide is irrelevant to the pathology of heart disease. People don’t die because cardiomyocytes divide and lose telomeres, they die because the cells lining the coronary arteries divide and lose telomeres. Likewise, people don’t die because heart muscle cells accumulate cholesterol, they die because the coronary arteries accumulate cholesterol.
The same is true with regard to Alzheimer’s dementia. Neurons may not (generally) divide nor their telomeres shorten, but microglial cells divide continually and their telomeres do shorten with age. Microglial telomeres shortening correlates with Alzheimer’s disease and appears to precede the onset of amyloid deposition and other hallmarks of the dementia. Central neuron function is critically dependent upon microglial function in the same sense that cardiomyocyte function is critically dependent upon the function of coronary vascular endothelial cells. In both cases, the neurons and the cardiomyocytes are the “innocent bystanders” in the pathology and in both cases the pathology begins in cells that show telomere shortening with age.
These two major age-related human diseases – atherosclerotic disease and Alzheimer’s dementia – are both examples of “indirect pathology”. The pathology of the end organ – dead myocardium and dead neurons – is indirect and is due to primary pathology that occurs in other cells, in this case the vascular endothelial cells and the microglia.
There are also a host of “direct pathologies”, in which the cells that divide and lose telomeres are also the very cells that underlie the final pathology. In the case of osteoarthritis, for example, the cells that divide and lose telomere length – the chondrocytes – are the same cells whose loss defines the actual clinical disease – the loss of joint surface. Direct pathology includes osteoarthritis, osteoporosis, immune senescence, skin aging, and a number of other clinical problems. Of course, in most of these diseases, there are interactions with other body systems that may play a significant role. For example, skin aging is due to cell aging of the primary skin cells – keratinocytes and fibroblasts for example – but it is also partially due to the loss of small vessels throughout the skin as the vascular endothelial cells age. The same is almost certainly true of most dementias, which often have a vascular component, whether because of decreased blood flow, micro-infarcts, or micro-hemorrhages. Although pathology is rarely simple, the rough distinction between indirect and direct age-related pathology will prove useful as we move into the realm of clinical intervention using telomere extension.
Misconception #6: Telomeres “cause” aging
Telomeres no more “cause” aging than the engine of your car “causes” you to get to work in the morning. More critically, the use of the word “cause” usually represents sloppy thinking, either because the word is simply wrong or because the underlying processes are so complex and sophisticated that simply referring to “causation” is entirely misleading. If two things are correlated, we should say so, rather than assume causation. If the relationship is actually a cascade of events, a complex web of processes that really does involve “causation” (rather than just correlation) then we need to be extremely careful in using a naïve word to represent a far more sophisticated reality. Cholesterol, for example, doesn’t actually cause coronary heart disease, but it does a significant role within a complex cascade of pathology. As part of this complexity, remember that some people with low cholesterol have significant coronary disease (e.g., progerics) and other people with critically high cholesterol may not have any measurable coronary disease. Causation is rarely simple.
Finally, causation is often not the issue and discussing causation at all (even carefully), often misses the point. This is particularly true in the case of human disease, where the key question is “what causes this disease”, but rather “can we intervene?” In the clinical world – the world of real patients and their health problems, intervention is the primary concern and causation plays a role only where it contributes to intervention (which it usually does, but again, only secondarily because it helps intervene). The issue of causation is not primary and is relevant only as it support the primary question of intervention. Many people have disagreed with the statement that telomeres “cause aging”, but they seldom understand either the data, the complexity, or the primary issue. Aging is full of correlations that result in misattribution of cause; aging is enormously complex with an interacting web of causation behind every definable pathology. Moreover, the primary clinical issue is intervention rather than causation, which is only a contributory (even if necessary) issue.
In this sense, discussions of causation are bootless exercises in philosophy (except as they further intervention), better reserved to conversations over wine than reasoned discussions of science or medicine. The most common issue with causation per se, however, is that many prominent “theories” of aging aren’t actually testable. One of the critical characteristics of the contention that telomeres play a central role in (not “cause”) aging, is that not only does all current data support this contention, but that we can actually test the theory both in vitro and in vivo. Not only does this result in good science (a non-testable theory isn’t science), but it meets the criteria for good medicine (we can use it to help patients get healthier).
Date posted: 01.10.2013
Reversing Human Aging was the first book in history to describe how aging works, how to reverse it, and the consequences of doing so. Originally published in 1996, it has largely passed the test of time. On October 1st, I published an electronic edition of this book on Amazon.com and made it available for those interested in the work of Double Helix Corporation. The new edition, however, was taken directly from my original manuscript as submitted for publication, rather than from the publisher’s final version as actually printed. To the contrary, it retains the uncorrected style of my initial writing. Using the original manuscript is sometimes a boon, as the original phrasing and word choice was – in some cases – pithier and livelier than the editor’s choice. In other cases, and in other opinions, the editorial changes were probably the wiser choice, but have still not been used in this version. In any case, while I wrote the book electronically and kept electronic copies, the publisher did not and only my original version is easily available in an electronic format. I have made no attempt to update (or correct) the science behind this version. Specifically, I have not used more current information about telomerase and human disease to alter my original statements, nor was it necessary.
For those who want more academic information, I refer them to my textbook, published in 2004 by Oxford University Press, Cells, Aging, and Human Disease. Like all information, whether hardcopy or electronic, it has also gone out of currency, although it certainly is more definitive and detailed than is Reversing Human Aging.
I am currently working on another, newer, updated book on reversing aging, also aimed at the public. I strongly feel that if you cannot explain a subject to the general public, then you don’t understand it yourself. Most academic writing only supports this opinion. While I find the project worthwhile and useful for me as I try to understand the area better myself, no book can substitute for investigation and compassionate intervention.
With this in mind, my priority has always been to move the field from the laboratory to the clinic, “from chromosomes to nursing homes”. Various forces – all firmly grounded in human nature – have conspired to prevent progress. Fortunately, recent advances have made action practical and other forces – again, human nature – have serendipitously come together to give us a chance to prevent and cure the diseases of aging by resetting the aging process at the genetic level. The vagaries of human nature should not and do not undermine our determined compassion and the wish to improve the lives, the joy, and the grace of those with whom we share the honor of being human. Humans may be a rum lot, but I’m one of that lot. If we can cure disease and remove the fear and tragedy that too often creeps into our souls with age, then we should do so. The key to such intervention – or the side effect if you favor irony – is to do what has never been done before: to reverse human aging.
And so we will.
Date posted: 17.09.2013
What is aging?
The question has always been hard to answer, making it difficult to change the process, let alone to reverse its clinical progress. Unfortunately, much of the problem derives from the way we look at aging in the first place. Making the wrong assumptions, we arrive at the wrong conclusions.
While human beings have the unique ability to routinely employ metaphor and analogy as cognitive tools, using the wrong analogy is – to use an analogy – like trying to saw wood with a hammer. Use the wrong tool and we produce completely useless furniture. In aging, not only do we usually choose the wrong analogy and naively assume we have an understanding of aging, but the outcome is seldom useful. While “theories” of aging abound, many are not only at variance with available biological and medical data, but they are sadly untestable to boot. Theory may be an aid to understanding, but when it can’t be falsified, it isn’t theory, it’s illusion.
As a physician, my goal is not simply theory, but intervention. If we can’t test it and we can’t use it in a clinical trial, then it may be entertaining philosophy, but it’s neither good science nor useful medicine.
One of the most pernicious analogies found among scientists and lay people alike is the notion that aging is like rusting. After all, I age and my car rusts, so what can you expect? Things get old and there’s nothing anyone can do about it, is there? You’re going to rust.
Wrong analogy: people aren’t cars and aging isn’t rusting.
As a slightly better analogy, consider your cell phone – a common piece of technology that we all use on a daily basis. Does your cell phone get old and fall apart – does it “rust”? Most of us have no idea, because – unless we break them – we almost always trade them in long before they actually fall apart. In fact, the way our cell phones “age” is a good analogy to the way our bodies age. Most cell phones get traded every few years, regardless of whether they’re working or not. Our bodies do almost exactly the same thing: most of our molecules get “traded in” every few days, regardless of whether they’re working or not. Your body is continually “trading in” molecules – recycling if you will – and the result is that most of your molecules are “new” and they work quite well.
At least, that’s true when you’re young.
But as you get older, the rate of recycling – like cell phones being traded in every 10 years instead of every year or two – gets slower and slower. The reason your body ages is not that the molecules “go bad”, but that the trade-in period gets longer and longer, with the result that it gets harder and harder to find molecules that work. So if you have a thousand molecules, almost all of them work when you’re ten years old, but perhaps only half of them still work when you’re one hundred. Imagine a thousand people with one year old cell phones: almost all of them work fine. But if they all have ten year old cell phones, most of them are worthless.
The problem is not that molecules – or cell phones – get damaged, but that the rate of recycling gets slower and slower as we get older. It’s not the rust, it’s not the free radicals, it’s not the day-to-day damage, it’s the steadily decreasing rate of repair and recycling that makes you old. The rate of repair is set by telomere lengths, which are in turn controlled by a number of things, but mostly be cell division. Every time your cells divide, the telomeres shorten, and every time your telomeres shorten, the rate of repair and recycling goes down another notch.
But what if we re-extend the telomeres? When we do exactly that – in the laboratory – human cells act young again. The cells repair the damage, the recycling rate climbs, and the cells reset the aging process. Moreover, when we try the same thing with human tissues – in the laboratory – we end up with tissue that looks and acts like younger tissue. Can we do the same thing, not in the laboratory, but in people? Can we reverse aging and prevent the diseases of aging?
Until recently, the problem has been to find a way to relengthen telomeres in all of those billions of cells that trigger age-related diseases, including the cells in your brain, your heart, and your joints. For the past seven years, there has been an informal human trial of several relatively weak oral compounds – astragalosides – that work indirectly to lengthen telomeres. The results suggest that we can not only lengthen telomeres, but we can show that parts of the body – the immune system – begin to act younger and more effectively. What we need, however, is a way to directly lengthen telomeres in all the cells that trigger diseases such as Alzheimer’s dementia, heart disease, strokes, osteoarthritis, and others.
Our role – at Double Helix – is to cure and prevent disease. Over the past twenty years, we have identified the tools we need to reset telomere lengths, reset the cellular aging process, and intervene in human disease. Now it’s time to come out of the lab and into the clinics.
It’s time we use compassion and hard work to create healthy lives.
Date posted: 27.08.2013
Almost twenty years ago, I gave a talk at the National Institutes of Health and had the audacity to title it “Reversing Human Aging”. Looking up at a packed audience, I said the following:
When I’m done, anyone who leaves this room thinking we can reverse human aging is a fool. Likewise, anyone who leaves thinking we can’t reverse aging is a fool. If any of you have any sense, you’ll leave here saying that you don’t know if we can reverse aging or not, but you need to see the data.
A week ago, I ran into a new book [Adam Leith Gollner’s The Book Of Immortality], an expose of those pursuing immortality, as well as the cults and the “industry” generally. The gist of the book was that the world abounds with charlatans who think they can (or who want you to think they can) reverse aging and let you live forever.
Forever? The world has far too many con men and an unending supply of fools.
On the other hand, there is a universe of difference between the idea of reversing human aging (a scientific question) and the idea of immortality (a theological question). We may well be capable of reversing human aging – we can certainly do it in the lab, but we are incapable of immortality and not simple for technical reasons. Reverse aging, maybe. Immortality, no. You and I are going to die, although the when and the how remain, perhaps thankfully, a little unclear.
Reversing aging – and curing age-related diseases – however, is not the same as immortality.
Just because we may be able to reset the clock of biological aging does not mean that you can survive jumping off a cliff, dangerous driving, living in a war zone, starvation, or Hamlet’s “thousand natural shocks that flesh is heir to”. Nor will reversing aging make you any saner than Hamlet was. If we can reverse aging, it certainly won’t give you immortality. On the other hand, the good news is that you may avoid Alzheimer’s dementia, strokes, heart disease, osteoarthritis, and all the other diseases that undermine our lives and our spirits as we grow older. Preventing age-related disease is fair enough as a goal and, as it turns out, is probably feasible.
Even though reversing aging has nothing to do with immortality, preventing the diseases of aging and reversing the aging process are inextricably linked at the genetic level. To put it concretely, there is no way we can prevent your brain from aging (Alzheimer’s dementia) or your heart from aging (atherosclerosis and heart attacks) unless we can prevent the rest of you from aging at the same time. Which means that if we reverse aging – and extend your healthy lifespan – the only way we can do so is by ensuring that you won’t end up living in a nursing home with dementia, heart disease, bad hips, and shortness of breath.
Fair enough: none of us particularly yearned to live in a nursing home anyway.
Until now, all of the advances in human lifespan have merely kept us from dying young. The phenomenal increases in the mean lifespan were simply due to more people making it into middle and old age, and not due to our ability to alter aging itself in any way whatsoever. We have cut down on infant mortality, infections, trauma, starvation, and a host of diseases of the young and middle-aged, enabling most of us to live long enough to encounter the diseases of old age. Now, instead of dying of polio and childbirth, we die of vascular disease, cancer, and Alzheimer’s disease. Worse yet, current estimates suggest that even if we could treat only vascular disease and cancer as individual problems, we’d all end up with Alzheimer’s disease. We would, as it were, go from the frying pan into the fire.
But what if, instead of treating merely the outcomes of heart disease, we could prevent the epigenetic changes that underlie the aging process at the most basic level and thereby prevent all age-related diseases? What if we reset the aging process by resetting the pattern of gene expression that underlies those diseases? While you would still have infection, trauma, inherited disease, and all of the other “natural shocks” of our lives, we would no longer be forced to succumb to the diseases of aging. This is precisely what we would like to do. We won’t offer immortality or many other things, but we can prevent suffering, pain, and that loss of the human soul that is the final flow of the aging process.
We can try to give people back their lives.
Date posted: 11.03.2013
Looking back on aging
Until quite recently, the notion of reversing human aging was mere fantasy, absent any scientific support. Throughout history, going as far back as the Epic of Gilgamesh 4,700 years ago , we have dreamed of being able to cure aging and the diseases that accompany it, but every claim of a “fountain of youth” has proven to rely on nothing more than false hopes and – more often than not – an urge to profit at the expense of the gullible. The fact that we never really understood aging, made it extremely unlikely we could learn to slow, prevent, or reverse the process.
Today, however, we stand at a unique point in history, much like where we were in 1870 with regard to infectious disease. At that time, few had heard of Pasteur or Koch, and well-known scientists ridiculed the idea of microbes being dangerous or causing disease. Time passed, however, and once ridiculed or not, we now take the concept of infectious disease for granted. In fact, much of what is good about modern medical care – sterile technique, antibiotics, immunizations, etc – derives from this single, powerful conceptual revolution that began a hundred and thirty years ago. Before we came to grips with the fact that microscopic creatures could harm and even kill us, effective intervention in most common diseases was also fantasy. In those days, treatment for tetanus infection, “lockjaw”, was a matter of early cauterization to remove
devitalized tissue (using a red hot iron rod or boiling oil), amputation if things got worse (without anesthesia), finally followed by hope, prayer, and attentive nursing care, though nothing really improved the deadly outcome. During America’s Civil War, roughly 60% of military deaths were attributable to tetanus alone, with other infections playing a lesser, though still substantial role in the devastation of human life. In wars, direct death due to trauma alone was relatively rare, partly because of the low kinetic energy of the weapons then in use, but largely because of the stunning risk of wound infection even after the most trivial injury. The merest scratch could cause slow unavoidable death. Not only was infectious death unnecessarily common, but the link between such deaths was completely missed. We think of malaria, cellulitis, tetanus, pneumonia, and yellow fever as a short list of infectious diseases; to the physicians of those times, each of these diseases was independent and unique, without shared mechanism, and without hope of effective treatment.
Today, we have much the same conception (and misconceptions) of aging and age-related diseases. We think of cancer, atherosclerosis, osteoporosis, osteoarthritis, skin aging, and immune senescence as all unrelated, except chronologically. You get these diseases as you get older, not because they have anything in common, but “just because you get older”. Even pathologists rarely consider common mechanisms, cellular events which link each of these diseases at the genetic level. After all, what could osteoarthritis and atherosclerosis, aging skin and Alzheimer’s possibly have to do with one another except that they happen to old people? Yet, not only do they share a great deal in common, but it is precisely this common thread that will allow effective intervention both in age-related diseases and in aging itself.
Old cars, old cells, and new free radicals
To understand the common mechanism, we first need to understand how aging itself occurs. To many, aging is simply a matter of wear and tear. Although often expressed in the scientific jargon of free radical damage to proteins and DNA or of reactive oxygen molecules and mitochondria, a simple homely model is often that of the aging car. Some scientists view getting old as the same thing that happens to a car, as it gathers rust, loses power, and falls apart . The problem with the car analogy is that organisms aren’t cars. What car can continually repairing itself for decades? If organisms were cars, then they would be remarkably wondrous cars with invisible, elf-mechanics that magically repair, replace, and tune up the car all the time. Imagine having a car in which every time a rust spot began to appear, the fender was magically replaced with a new one. Every time the tires lost a bit of their tread, the elves magically added more new rubber with deeper treads. Every time the spark plugs got dirty, the elves took them out, cleaned them, shined them, adjusted the gaps and replaced them. The oil was replaced every night, the paint redone every two days, the engine cleaned and tuned once a week. Magical, yes, but that is precisely what your body does all the time. You live in a body that actively resists wear and tear by continually repairing itself, replacing lost cells and damaged proteins, making new mitochondria and new molecules, fixing DNA and remaking itself from top to bottom. Quite some car.
And yet, this magical car, this body which continually repairs itself, grows old. The problem, however, lies not in the rust and the worn tread, but the fact that it stops repairing itself. There is always free radical damage, but older cells stop doing much about it. Every single one of your cells divided and ultimately came two joined cells, one from each of your parents (with the mitochondria from your mother), whose cells in turn came from their parents, and so on back as far as life has been around. Following your cells (and their mitochondria) back through your maternal line, we quickly realize that you are part of a line of cells which are three and a half billion years old. You look pretty good, considering that free radical damage has been after your cells for several billion years. Why haven’t those cells aged and died? Perhaps its not just free radical damage, but something about fertilization and having so many cells. But there are multicellular organisms that never age and single celled organisms that do. In fact, the reason that your cells age is that they allow themselves to do so.
Some cells, cancer cells or the germ cell lines that created you, never age. Other cells, such as most (though not all) of the cells of your body age, although at varying rates. All of these cells – aging or not, at different rates or not – are exposed to free radical and other damage, yet only certain cells age. The difference is that aging cells slow down their repair (and other) processes, which cells that don’t age continue to deal with the damage, quite literally forever.
Let’s look at what kinds of damage we are talking about, even just narrowing it down to free radical damage. Almost all (about 92%) of free radicals are made in your mitochondria. The first problem, then, is trying to avoid making free radicals. Unfortunately, since we need oxygen to survive, we can’t avoid making a least a few free radicals as we make ATP, the molecule that fuels almost everything in your cells. Worse yet, as your cells age, they make more and more free radicals for the same amount of ATP. In other words, your cells get sloppier as they get older.
The second problem is keeping the free radicals away from things that you need. It’s bad enough making free radicals within the mitochondria, but the last thing you want is to expose your DNA and critical cell proteins to attack from these dangerous free radicals. Luckily, your cells (like all eukaryotic cells) hides the DNA in a safe place – the nucleus – and tries to keep the free radicals in another – the mitochondria. But as your cells get older, the lipid membranes begin to leak: the free radicals begin to escape from the mitochondria.
The third problem is catching and breaking down those escaping free radicals. Your cells use vitamin E, superoxide dismutase and a number of other mechanisms to deal with free radicals. Unfortunately, as you get older, all of these mechanisms become a bit less available. As a result, free radicals roam about more freely and do more damage in older cells than they did in younger cells.
Finally, no matter how good your cells are otherwise, there is always some damage that your cells have to deal with. In the case of DNA, you repair it, in the case of everything else, you replace it. Unfortunately, as your cells age, all of this slows down too. The result is a gradual increase in the likelihood of damaged DNA, proteins that don’t work, and membranes that leak (as above).
Together, these four problems are a guarantee that your cells will slowly fall apart and fail to work, resulting in tissues that don’t work, resulting in a body that doesn’t work, resulting in problems for you. The obvious question is what we might be able to do about any of this. You could try to fix any one of these problems. For example, you might use caloric restriction to limit the production of free radicals. Or you could increase your dietary vitamin E to help scavenge the ones that escape. Both of these, and most other approaches deal with only a single part of the problem and, worse yet, only with problems after they have occurred. The best approach would be to deal with all of the problems and not just by “cleaning up after them”, but by stopping the entire problem at the cause. But is there really a single place to intervene?
Repairing cells with your own genetic toolbox
Curiously enough, all of the problems come together in one single place: gene expression. All of the changes listed above, and a lot of others, occur because the pattern of gene expression changes as we age. Your genes are just the same, but the what they do certainly isn’t. Just as the difference between a muscle cell and a skin cell is the pattern of gene expression, so too is the difference between a young cell and a young one. But what controls that pattern and, more importantly, can we do anything about it?
The list of things that affect gene expression is enormous. Every cell affects its neighbors and hormones, diet, activity, infections, and a host of other things affect gene expression. In fact, the list is practically infinite: almost everything affects gene expression to some degree in a cell somewhere in your body. Even the much smaller list of things that control the change in pattern of gene expression between young cells and old ones is remarkably long. Luckily, however, we know of one thing that appears to be the major control of that change, namely the telomere.
The telomere is a long piece of DNA at the end of each one of your chromosomes. Because of the way DNA is replicated , , every time one of your cells divides, it loses a small part of its telomere. This gradual loss causes a change in the proteins around the telomere which in turn causes an indirect change in gene expression throughout the rest of the chromosome. The overall result is simple: every time your cells divide, they get a little bit older. Although some of your cells – nerve and muscle cells, for example – don’t divide very often, this doesn’t protect them. In each case the cells that don’t divide (and so don’t age much) are dependent on cells that divide quite a bit. In the case of heart muscle cells, for example, it is not the heart that ages, but the arteries supplying the heart. In the coronary arteries that supply the heart muscle, the cells lining the vessels – the vascular endothelial cells – not only divide, but do so all the more in the face of smoking, high blood pressure, diabetes, and other things known to cause atherosclerosis. In short, the reason that most cardiac risk factors cause heart attacks is because they make the cells that line your arteries divide and age.
In each organ, we can trace aging diseases to aging cells. In Alzheimer’s disease, it is the microglia that appear to be the culprit. In arthritis, is the chondrocytes that make up the cartilage in your joints. In your bones, the osteoblasts age and result in osteoporosis. In your immune system, the lymphocytes age and result in poor immune function. In your skin, the fibroblasts and keratinocytes age and result in thin and wrinkled skin. In every organ, in every tissue, in every disease, we find dividing cells, aging, changing, and failing.
None of this would be of much importance if we couldn’t prevent the failure, but, as it turns out, we can. The first study that showed we could prevent aging in cells came out only a few years ago. Since then, the same result has been repeated in a host of other laboratories and other cell types. At the cellular level, reversing aging is well within our current ability.
None of us, however, are mere cells, but tissues, organs, and bodies: vast collection of cells, each cell with a specific function and each dependent upon all other cells. While we can reverse aging in cells, can we go further and reverse aging in tissues or entire organs? In a sense, we already have. We can now reset aging in reconstituted human skin. If we take a mouse and transplant human skin cells (keratinocytes and fibroblasts) onto it, the cells layer out and grow human skin. If we use young human cells, we get young human skin: with thick and deeply interdigitated layers, strongly bound together between the dermis and epidermis. If we use old human cells, we get old human skin: with thin and barely adherent layers, weakly bound between dermis and epidermis and prone to sloughing off at the least pull. But is we take old human cells and reset the pattern of gene expression, the result is, once again, young skin; the skin is thick, the layers have deep interdigitations, and the cells are typical of young skin both in terms of their gene expression and their histology . The age of your skin is not a matter of how old the cells are, but of how old the gene expression is.
From nursing homes to chromosomes: actually reversing aging
Just as the telomere is the key to the altered pattern of gene expression in aging cells, so too is it the key to resetting gene expression in cells and in reconstituted human skin. Here, as always, the question is not “What causes aging?”, but rather “What is the single most effective point to intervene in aging?” The issue is not academic, but concrete. How can we most effectively and efficiently prevent or treat the diseases of aging? In treating arthritis, we could (and do) replace the affected joints, but this is painful, expensive, and not entirely effective. In treating heart disease, we could replace the heart itself, but this is not only painful and expensive, but remarkably risky as well. In treating the genes that underlie these and other age-related diseases, we could – just as with hips and hearts – replace the affected part. But just as in hips and hearts, so too with genes: why not simply make the normal part work the way it was intended to work? The difference between a young cell and an old cell is not the superoxide dismutase gene, nor should we replace this or other genes. The difference between a young cell and an old cell is that this and other genes are not being expressed in the right amounts and at the right times. All of this can, and has been reset by using telomerase both in the laboratory and in reconstituted skin.
The current question is what is the best way to reset gene expression to that of normal young cells. We could replace the telomerase gene, which would then express normal telomerase, reset the genes, and rejuvenate normal cell function. Even better, however, would be to control the existing telomerase gene in each of your cells, turning it on and off as needed. This is the role of a telomerase inducer, currently under development. Either of these techniques – inserting another copy of the normal telomerase gene or using a telomerase inducer – should do the trick.
Gene insertion has already been used in other contexts and human trials using telomerase are not far off. Using this technique, a gene gun can be used to fire millions of copies of the human telomerase gene (hTERT) into human skin. While the “take” for this technique is normally fairly low, it would be sufficient. Dermal and epidermal cells would take up the hTERT gene and begin expressing it, resetting gene expression, and returning to normal young adult cell function. Current plans call for attempting this in four different types of patient: those with Fanconi’s anemia, those with dyskeratosis congenita, normal older patients in a wound care center, and children with Hutchinson-Gilford progeria. In the first two diseases, patients are known to have difficulty maintaining normal telomere function. In Hutchinson-Gilford progeria, the cells lose telomere length early in life, at least in the blood vessels, skin, hair follicles, and joints. The result is that these children have atherosclerosis, thin skin, little hair, and arthritis, usually dying by age 13 of a heart attack or stroke. Small wonder we might want to try fixing the problem.
In the case of normal older patients, we may try inserting a normal hTERT gene into the skin, particularly around the pressure sores these patients typically have. These are the result of poor innervation (so the patient is often unaware of sitting on them for hours), poor circulation (so they easily get infected and have a poor oxygen supply), and poor skin function (so the cells are slow to divide and heal the lesion). If we can repopulate the skin with healthy cells, the sores may heal more quickly and fully than is normally the case in the elderly.
The real question, however, is what happens if we try these approaches in normal, older patients even without skin sores. Moreover, we could try a similar approach in coronary arteries (the cause of heart disease), glial cells in the brain (which may underlie Alzheimer’s dementia), chondrocytes in the joints (which cause osteoarthritis), osteoblasts in the bones (which fail in osteoporosis), lymphocytes in the blood (which cause immune aging), etc. Both these trials and trials using telomerase inducers are likely to begin within the next few years. Only when we are finally able to intervene in the fundamental causes of aging – the altered pattern of gene expression that permits your cells to finally succumb to free radicals and a host of other problems – will we finally be able to reverse human aging and prevent the suffering that accompanies the diseases of aging .
Date posted: 27.02.2013
Telomere lengths can serve as useful clinical biomarkers. Several of us have suggested this point since the mid 1990′s and my 2012 article on this potential (Use of telomere length as a biomarker for aging and age-related disease) clarified the pro’s and con’s of this area. More recently (February 2013), an article in JAMA showed that telomere lengths serve as a biomarker for immune responses, specifically to URI’s in human patients.