Towards A Unified Theory Of Aging And Cancer
In my work, I spend a lot of time thinking about cancer. In toxic exposure and pharmaceutical lawsuits, I have to prove, with a bevy of experts, that a given chemical or drug is capable of causing cancer. In medical malpractice cases involving undiagnosed cancer, I have to prove the cancer was treatable at an earlier stage, and prove how that treatment would have made a difference. I’ve spent hundreds of hours discussing cancer with oncologists, cell biologists, biochemists, immunologists, epidemiologists, and biostatisticians.
So pardon me as we depart from the law in this post and talk about the science of cancer and aging.
Two weeks ago, The New York Times Magazine had an extensive feature on cancer. The basic story is simple enough: “cancer” isn’t really a single disease at all, not even within the same organs, but rather is the result of a constellation of genetic mutations (with great variability between cancers even of the same organ) and changes in cell metabolism and function. We’re getting better at “individualizing” treatment for each particular cancer, and we’re realizing that we may need to focus more on the metabolic problem than on the genetic mutations.
None of this is breaking news. Back in 2000, Douglas Hanahan and Robert Weinberg proposed the “hallmarks of cancer,” the primary traits that cells evolved progressively as they turned into tumors and, eventually, malignancies:
- Sustaining cell proliferative signaling
- Evading growth suppressors
- Activating invasion and metastasis
- Enabling replicative immortality
- Inducing angiogenesis
- Resisting cell death
In 2011, they added three more “emerging” hallmarks of cancer:
- genome instability and mutation
- tumor-promoting inflammation
- reprogramming energy metabolism
Presumably, if we get better at fighting each of these “hallmarks” — e.g., combatting the reprogrammed energy metabolism of cancers — we can “cure” cancer.
Jarle Breivik, professor of medicine at University of Oslo, spoils it all:
The growing cancer epidemic is not a problem that medical science is about to solve. In fact, it is a problem we are about to make worse. The better we get at keeping people alive, the older they will get, and the more cancer there will be in the population. …
[C]ancer and aging are two sides of the same coin. The risk of getting cancer increases significantly with age, especially after the age of 50. Accordingly, the longer we live, the more cancer there will be, and regardless of medical advances, we can be very sure that the burden of cancer will increase, not diminish, for decades to come.
Curing cancer without curing aging does present the tragic paradox of extending life for a few years in which a person is at an increasing risk of cancer in general and a substantial risk of developing the same cancer again. Prolonging life even by a few years is useful in its own right (we can debate at what point the cost of a given extension is ‘worth it’ to society), but it is certainly not “curing” cancer.
But the very reason Breivik cites for his pessimism — that “cancer and aging are two sides of the same coin” — may also be the reason for optimism. If they’re two sides of the same coin, then, perhaps the treatment of cancer can give us clues about aging itself. Perhaps we can treat them both.
Aging and Cancer: Two Sides Of The Same Coin
The single best predictor of how long you have left to live is your age. This sounds like a truism, one of those just-so facts unworthy of further investigation — and there are plenty of scientists who pounce on the term “anti-aging” whenever it is used — but there is no obvious reason why cancer and cardiovascular disease should be rare before 35 years of age but then the overwhelmingly likely causes of death thereafter. There is similarly no clear reason why, after 45, cancer is the more likely cause of death but, then, after 75, cardiovascular disease takes over.
We have only just begun to understand what aging is, why it occurs, and if we can do anything about it. Last week, Nautilus had an extensive feature on aging. Aging is now understood as more than just ‘the ravages of time.’ For reasons we still don’t quite understand, the human body does a phenomenally good job at maintaining itself until about 30 years of age, after which it increasingly gets worse at maintaining healthy cells and loses the complexity of its structures.
If you can identify the root causes of cancer and aging, maybe you can mitigate them or prevent them entirely.
There’s ample reason to believe that many “age-related diseases” aren’t unique entities, and that aging itself is the better issue to examine than the diseases alone. As a team of researchers wrote in Cell in 2014,
Interrogating and developing therapeutics for one disease at a time has often been productive. Will, however, the success of this approach be sustainable for the chronic aging diseases, such as neurodegenerative and metabolic syndromes, most cancers, and cardiovascular disease? Findings in the last few decades have made it impossible to ignore the integrative nature of human physiology. Pathologies thought to be disparate are now understood to be connected.
They identified seven “pillars of aging,” each connected to one another:
- adaptation to stress
- macromolecular damage
- proteostasis (a portmanteau of “protein” and “homeostasis”)
- stem cells / regeneration
If these sound familiar, it’s because several of them line up directly with the “hallmarks of cancer” identified above. Inflammation is, unsurprisingly, both a “pillar of aging” and a “hallmark of cancer.” Same with metabolism. Indeed, virtually all of these “pillars of aging” can be reframed as “hallmarks of cancer.” It’s no coincidence that, as we “age,” we are more likely to develop cancer — the underlying processes are not just similar, but are often the same.
But, when it comes to slowing, halting, or reversing “aging,” there are doubters here as well. Peter Hoffman, professor of physics at Wayne State University, is unimpressed, and he raises the specter of entropy itself inevitably destroying the body:
[As we age, the] loss of fidelity and increase in disorder will manifest itself—by its very nature—randomly and therefore differently for different people. But the ultimate cause remains the same.
If this interpretation of the data is correct, then aging is a natural process that can be reduced to nanoscale thermal physics—and not a disease. Up until the 1950s the great strides made in increasing human life expectancy, were almost entirely due to the elimination of infectious diseases, a constant risk factor that is not particularly age dependent. As a result, life expectancy (median age at death) increased dramatically, but the maximum life span of humans did not change. An exponentially increasing risk eventually overwhelms any reduction in constant risk. Tinkering with constant risk is helpful, but only to a point: The constant risk is environmental (accidents, infectious disease), but much of the exponentially increasing risk is due to internal wear. Eliminating cancer or Alzheimer’s disease would improve lives, but it would not make us immortal, or even allow us to live significantly longer.
He may have a point. Consider this frustrating passage from a recent paper: “An enduring possible explanation for aging is the oxidative stress theory. Although there is solid evidence showing that oxidative stress is a contributor to some aging pathologies, lifespan extension has yet to be consistently achieved through strategies to mitigate levels of oxidative damage.”
Add to that the ample research showing that, although fruits and vegetables are ‘good for you’ for a host of reasons, there’s no clear evidence antioxidant supplements will do anything useful. In fact, there’s evidence that some of them (beta carotene, vitamin E, and vitamin A) might actually be worse when used in high doses, and might increase the risk of some cancers. A trial of beta carotene in smokers had to be stopped when they found a substantially increased risk of lung cancer with its use.
Why Does The Human Body “Go Over The Hill” After Thirty?
The problem with Hoffman’s analysis, however, is that, from a physiological standpoint, humans are virtually immortal for their first thirty years of life. As Josh Mitteldorf and Dorion Sagan point out, a 20-year-old has a 99.9% chance of surviving the next year. Despite twenty years of the ravages of thermodynamics on a “nanoscale” level, their bodies are fully capable of maintaining themselves, removing damaged tissues and replacing it with healthy (sometimes healthier) substitutes.
Indeed, it seems human peak performance occurs in the time between age 20 and age 30:
Generally speaking, athletes start to see physical declines at age 26, give or take. (This would seem in line with the long-standing notion in baseball that players tend to hit their peak anywhere from ages 27 to 30.) For swimmers, the news is more sobering, as the mean peak age is 21. For chess grandmasters, participating in an activity that relies more than mental acuity and sharpness rather than brute, acquired physicality, the peak age is closer to 31.4.
For setting world records in a given athletic discipline, the mean age is 26.1…
If, as Hoffman noted, aging was a fundamentally due to “nanoscale thermal physics,” then surely a quarter century of it would be more than sufficient to wear down people’s bodies. And, yet, people get better, faster, stronger, and smarter — until they hit their thirties.
Performance declines and mortality rises when a person hits 30: a 40-year-old has 0.002 odds of dying in the next year, double that of a 20-year-old. The rate steadily increases with each year, then accelerates rapidly after 60 years of age, doubling every 8 years: 0.01 at 60 years, 0.06 at 80 years, and 0.36 at 100 years.
Why? What makes a chess grandmaster’s mind better from 21 to 31, but worse from then on? Why do athletes’ bodies improve continuously until they’re about 26, then decline from then on? Why does the death rate accelerate as we age?
It would seem to ‘make sense’ that, over time, we ‘accumulate damage,’ but bodies aren’t like buildings or ships, built to specification from the beginning and then decaying over time. They’re in a constant state of renewal, a state the body can maintain quite well for thirty years, improving the whole time. The concept of ‘accumulating damage’ doesn’t explain why the human body does so well for its first thirty years and then suddenly gets worse and worse at handling the ordinary conditions of existence.
Something has changed. Switches have been flipped.
On the cellular level, aging has defied every attempt at an easy answer. In 2013, research proposed nine hallmarks of aging:
- genomic instability
- telomere attrition
- epigenetic alterations
- loss of proteostasis
- deregulated nutrient sensing
- mitochondrial dysfunction
- cellular senescence
- stem cell exhaustion
- altered intercellular communication
These line up with the “hallmarks of cancer” as well: when Hanahan and Weinberg themselves discuss this same genomic instability and telomere attrition as factors in cancer progression. Similarly, “cellular senescence” and “altered intercellular communication” play large roles in cancer biology.
Aging and cancer are, indeed, two sides of the same coin.
Telomeres and Epigenetics: Clues And Markers, But Not Silver Bullets
Two of those “hallmarks of aging” might have jumped out at you: “telomere attrition” and “epigenetic alterations.” Both have benefitted from extensive news coverage lately.
Precisely how bodies age is the domain of biological gerontology, which studies such events as the increased accumulation of somatic mutations, reductions in tissue elasticity, increase in autoimmune responses, and diminished length of telomeres (end-pieces of chromosomes that can be likened to the plastic tips at the end of shoelaces, and which evidently protect chromosomes as they undergo cell division). Most human cells poop out after about 60 or so replications, apparently in conjunction with the loss of telomeres, which become a bit shorter with every bout of mitosis—although it isn’t clear whether aging-related decrepitude results from this reduction in telomere length, or vice versa.
When DNA is copied, even if there are not any mutations, the “copy” isn’t exactly a “copy,” it’s a bit shorter because of the room needed at the end for the RNA used for copying. Having less DNA than you had before can mean, in theory, a less robust copy, one more susceptible to problems like mutations in the DNA code or inappropriate changes in gene expression. By analogy, shortened telomeres are like artifacts on a paper that has been copied and then had its copies copied and so on. You can’t do it forever without eventually leaving the paper unreadable; information has been lost.
There’s reliable science behind the role of telomeres in aging. A Danish study of 64,637 people followed over an average of seven years found that the people in the bottom ten percentile of telomere length had a forty percent greater chance of dying from any cause than the people in the top ten percentile of telomere length.
There’s some exciting research in which the length of telomeres in humans have been extended, but even that wouldn’t fix the problem of aging: Richard Cawthon at the University of Utah, who did the original telomere-and-mortality study back in 2003, believes that completely stopping telomere shortening would add between 10 and 30 years to our lives.
Adding 10 to 30 years of life would be an incredible achievement. At the same time, that’s an estimate of the greatest possible benefit we could get from completely stopping telomere shortening. That’s not the fountain of youth. Then there’s the big question about quality of life: curing telomere shortening would probably reduce the incidence of cancer and several other major diseases, but there are plenty of age-related diseases that show no consistent relationship to telomeres, like Parkinson’s. Telomeres have a relationship to Alzheimer’s disease, but a very modest one, to the point it is more a marker of the disease than a clear cause of it.
But let’s go back to that Danish study. The bottom ten percent in terms of telomere length had merely a 40% greater chance of dying than the top ten percent? This is a substantial difference, but it’s not mind-blowing, and the differences between someone with above-average telomere length and someone with below-average telomere length are trivial. A current smoker has a roughly 300% greater chance of dying compared to a never-smoker. Telomere length is more on par with the use of talcum powder, which increases the rate of ovarian cancer by 35%. It’s more like grade 2 or 3 obesity (BMI >35), which increases the rate of death by 29% percent.
Telomeres are plainly a part of aging, but they do not tell us the whole story, or even most of the story. Indeed, the latest research about telomeres shows how poorly they correlate with mortality:
Our aim here was to quantify the prognostic value of leukocyte telomere length relative to age, sex, and 19 other variables for predicting five-year mortality among older persons in three countries. … Age was, by far, the single best predictor of all-cause mortality, whereas leukocyte telomere length was only somewhat better than random chance in terms of discriminating between decedents and survivors. After adjustment for age and sex, telomere length ranked between 15th and 17th (out of 20), and its incremental contribution was small; nine self-reported variables (e.g., mobility, global self-assessed health status, limitations with activities of daily living, smoking status), a cognitive assessment, and three biological markers (C-reactive protein, serum creatinine, and glycosylated hemoglobin) were more powerful predictors of mortality in all three countries. Results were similar for cause-specific models (i.e., mortality from cardiovascular disease, cancer, and all other causes combined). Leukocyte telomere length had a statistically discernible, but weak, association with mortality, but it did not predict survival as well as age or many other self-reported variables.
In other words, knowing a person’s telomere length predicted far less about their mortality than just asking them a bunch of questions about their lives and doing some basic blood tests. A person’s telomere length tells us far less about when they will die than the most basic question: how old are you?
That brings us to “epigenetic alterations.” The term “epigenetics” is thrown around so much these days for so many issues that we need to start with a clear definition: epigenetics is the study of cellular and physiological changes caused by external factors that alter how genes are expressed or used by cells. In other words, they’re not mutations to the actual DNA sequence, but rather something outside of the genetic sequence that changes how the genes are used.
One of the key elements of epigenetics is DNA methylation, which functions to regulate gene expression and cell differentiation, which, in turn, are among the most important components of aging and cancer. As a review last year noted,
[T]here is a growing body of literature that supports an age-specific drift of methylation patterns. Not only are age-dependent methylation patterns surprisingly predictive for age within a range of two to four years, but such signatures could also be observed in aging mice and in patients with progeroid syndrome, a disease that has many features in common with aging.
Yet, as they also noted, “DNA methylation has become a hallmark of aging, though there is so far no proof that a change in specific DNA methylation patterns can extend lifespan.”
A separate study found DNA methylation can indeed predict mortality independent of “health status, lifestyle factors, and known genetic factors,” but, like with telomeres, the predictive value wasn’t great: using someone’s DNA methylation as a proxy for their biological “age” showed a 21% higher mortality risk when adjusted for only age and sex, and a 16% higher mortality risk when adjusted for socioeconomic (education, etc) and health-related (hypertension, diabetes, etc) factors. Like with telomeres, DNA methylation obviously represents something about the process of aging, but it isn’t a silver bullet, either.
This may change over time. Plenty of smart people in the field believe “that aging is caused by epigenetic changes, rather than the other way around.” Perhaps we’re not looking at the right places for methylation, or perhaps we’re not looking at them the right way.
The Unified Theory Of Aging And Cancer
So what’s the point of all of this?
First, to note where we are, historically, in the research on cancer and aging: near the middle. It is simply too early to make bold pronouncements about either the fountain of youth being just around the corner or about the inevitable failure of curing cancer or aging. We’ve conquered electromagnetism so thoroughly that we can build extraordinarily useful things like the computer you’re using to read this post. That didn’t happen overnight, but rather through centuries of work on electromagnetism. By analogy, when it comes to cancer and aging, we’re at a point more comparable to where we were in electromagnetism around the 19th century — we know a fair amount about the underlying processes at work (all those “pillars” and “hallmarks” above), but we haven’t yet sorted out the details, and we’ve just barely begun work on useful applications.
Second, to point out the obvious: it helps to live a healthy lifestyle. If you do nothing else but not smoke, drink in moderation, keep your BMI below 27.5, and exercise regularly, you’ll be rewarded with a substantially lower risk of cancer. You’ll feel better, too. Same goes with avoiding combining activities that are bad for you: “combinations involving physical inactivity, sedentary behavior, and/or long sleep duration and combinations involving smoking and high alcohol consumption were most strongly associated with all-cause mortality.”
Following the past half-century of press reports would have lead you to fear fat and then love it, to fear cholesterol and salt and then become indifferent to them, and to spend 90 minutes doing aerobics and then twenty minutes doing CrossFit. When all is said and done, the answers we have so far are pretty simple: eat well, exercise regularly, avoid smoking, and minimize drinking. The “best” mixture of carbs, fat, and protein, and the “best” types of exercise, are the ones you can stick to.