Aging, and the Cure of the Diseases of Aging

Posted by Michael Rae on April 24, 2013 | Chief Science Officer's Team

The diseases of old age. Age-related disease. The diseases of aging. We’ve all heard this language used by medical experts. But what do we mean by them? What is the mysterious connection between aging and the diseases of aging? And how is SENS Research Foundation targeting that connection to keep people healthy and prevent and cure the suffering of old age's diseases and disabilities?

While we sometimes prefer not to think about it, we all know that people lose their health as they age. Angina, Alzheimer's, breast and prostate cancers, chronic kidney disease ... With rare exceptions caused by birth defects, severe congenital mutations, or traumatic injury, these diseases are never present in young adults. Their first subtle hints crop up in the years between our forties and our seventies, accompanied by the weakening of our muscles (even in athletes), loss of cushioning in our joints, failing of the eyesight, and a generalized decay of the body's resilience and health. Over time, the minor aches and vague malaise of middle age devolve more or less rapidly into clinical diagnoses, leaving us with a rising burden of disease, disability, and dependence. But why does this happen? What is it about these diseases that causes them to slowly creep into our bodies after decades of relatively healthy life, each joining and building on the others, as if they were so many poorly-coordinated orchestra musicians, playing at different speeds, starting at different times, and raising a caucophany that gets louder and louder until it reveals itself as a terrible, secret symphony? And what can the answers to those questions tell us about what to do about them?

Things Fall Apart
Over the decades that you share life with friends and loved ones, you watch as the degenerative aging process gradually sets into young, healthy bodies, rendering them ever more fragile and riddled with age-related disease. Fundamentally, what you're witnessing is the same thing that happens over time to a new car that isn't optimally maintained. The immaculate finish of the new machine you drove home fresh off of the dealer's lot slowly begins to loose its lustre. Its upholstery fades. Its brakes slowly get soft. It develops leaks in the manifold gasket, and begins to exude the stench of a corrupted catalytic converter ... and eventually, the engine seizes up.

So it is with our bodies. During our first two to three decades of life, developmental programs build up our growing bodies, laying down the cellular and molecular structures of our tissues in exquisite fidelity to the instructions carried in our genetic code. From form, flows function: the pristine condition of the microscopic machinery of life ensures its silent, unimpeded functioning, manifested in the health and vigor in youth. But like a car or any other ordered system, the components of that carefully-organized structure can be damaged — not just by blunt trauma, with its visible scars, but at the microscopic level, during the course of normal cellular operation. The business of life is carried out by intricate, interlocking, tightly-regulated cycles of biochemical reactions in our cells, which must respond with perfect elasticity to the constantly-shifting demands of everyday life, as we eat, drink, sleep, go hungry, walk to work, or make love. But these dazzlingly-complex reactions have to be executed in the hurly-burly of living cells and tissues, rather than in the neat isolation of laboratory Petri dishes. So minor biochemical "accidents" that cause microscopic damage to the structure of our cells and structural molecules are frequent and inevitable events.

Just like the wear on an engine, the damage occurs at such low levels that you don't notice its effects at first: instead, it takes many decades for the damage to build up to the point where tissues begin to cease proper functioning. Thinning skin, clouding eyes, muscles sapped of strength, shortness of breath, failing memory … from minor malaise to crippling and life-threatening conditions, the diseases and disabilities of old age flow from the inexorable degradation of the integrity of the cellular and molecular machinery that carries out the essential functions of our tissues. And as some tissues stop functioning properly, other tissues that depend on their activity make increasingly-desperate attempts to repair, adapt to, or compensate for the rising tide of damage. As the originating organs continue to decay, these secondary effects become chronic and dysfunctional, leading to self-perpetuating inflammation, oxidative stress, and other metabolic aberrations that impair our health even more.

Aging: In Whole and In Parts
So aging is nothing more or less than the integrated, whole-body picture of these myriad forms of damage, decay, and dysfunction accumulating in all of our tissues over the course of time, impairing the ability of our cells and organs to keep us alive and healthy. When we look at someone and can see that she's old, what we are seeing is the sum of the outward ways that all of that damage has ravaged her body — her skin, and her hair, and her muscles — and the indirect signs, like the damage to her joints that shows itself when she struggles to button her coat, and the damage to subsets of nerve cells that surfaces in her trembling hand when she signs her name.

Age-related diseases, in turn, are nothing more or less than the many particular ways that particular organs and tissues stop working properly as a result of their lifelong accumulation of the particular forms of aging damage that most impact their ability to carry out their function in the body. "Alzheimer's disease" is just the name we give to a particular subset of the aging process that occurs in particular parts of the brain; "Parkinson's" is just the name for another such subset. Becoming more farsighted with time, as well as cataracts and age-related macular degeneration (the number one cause of blindness in people over the age of 65) are the aging of different tissues in the eye. Atherosclerosis is one manifestation of the aging of the arteries; the stiffening or "hardening" of the arteries that causes our blood pressure to slowly rise with age (and the risk of stroke along with it) is another aspect. Frailty (a recognized medical syndrome of aging) is the terrible late stages of the aging of the muscles, the bones, and most likely the skin and other cells that support these tissues.

But if all of this aging is happening in all of our organs and tissues throughout adult life, then why does one person seem to age more slowly than another? And why do some people develop particular age-related diseases — chronic kidney disease, or chronic bronchitis, or glaucoma, or heart failure — at earlier ages than other people do, and even though that same person may not develop other diseases of aging for many years after? Because the point at which a given tissue or organ reaches a level of damage that is beyond its ability to continue to function — the point, in other words, at which a particular age-related disease sets in — is determined by the sum of the multiple, largely independent sources of damage that occur in particular organs and tissues — and these multiple forces vary from one person to another, and in one tissue or organ and another within the same person. A given organ can be weaker than average at birth, because of unfavorable genes or its because its mother was missing essential nutrients in her diet. It can be injured in a car accidents or a skateboarding spill. Different organs can be particularly damaged by specific lifestyle exposures, like smoking (the lungs and circulation), or excessive alcohol (the liver and the brain), or overeating (the insulin-producing cells of the pancreas). It can atrophy for lack of use, whether it's muscles and hearts that never get exercised or a brain that never gets challenged. And just as Range Rovers are built to last longer than Chryslers, people do vary to a moderate extent in the rate at which even the most fundamental, inescapable aspects of aging occur. This is why longevity runs in some families: because of variations in genes that slow down the the rate of cell growth, or regulate metabolic processes involved in driving particular forms of aging damage, members accumulate moderately less aging damage over time, and as a result are able to put off the diseases of aging into their eighties instead of their seventies.

It's all of these things coming together that will determine when a given organ in a given person will cross over that critical threshold: when so many of its cellular and molecular structures have been disabled by damage, that it no longer has the functional reserve needed to carry out its role in the body in the face of the ordinary challenges of life. And once again: when that happens, we call it a disease.

Managing the Unmanageable
For decades, pharmaceutical companies have put all of their energies into tackling one kind of contributor to age-related disease. Understanding that the diseases of aging are driven by the accumulation of damaging byproducts of metabolic processes, they have chased after drugs that inhibit those same metabolic processes. The metabolic precursors of the particular kinds of damage that contribute to individual diseases of aging were christened “risk factors” for those diseases, and the goal of medicine was framed as “managing” the excessive burden of such risk factors. By pushing the body to produce less of one or more forms of disease-driving cellular or molecular damage, these drugs slow the accumulation of damage in a vulnerable tissue, and thus bend the curve of a particular age-related disease.

Atherosclerosis, for instance, first begins when toxic byproducts of cholesterol become trapped in cells patrolling our artery walls. Statin drugs force the body to produce less cholesterol; indirectly, this draws down the number of cholesterol-bearing particles circulating in your blood — and with fewer cholesterol particles circulating, fewer cholesterol particles become trapped in the artery wall, damaging it. By this means, statin drugs slow the rate of buildup of fatty plaques in your arteries.

Other drugs force the kidneys to release more water, or block the action of hormones that tighten the arteries, in order to bring down blood pressure. Lower blood pressure reduces the damage that the pounding of the pulse causes to the fine structures of the kidneys, and reduces the risk that the pressure will burst a blood vessel in the brain, triggering a stroke. Still other drugs manipulate the way that the body transports and metabolizes blood sugar in order to lower circulating blood sugar levels; lower concentrations of sugar in our blood slow down the formation of the sticky sugar bonds in our tissues that gum up the functioning of the eyes, kidneys, and arteries of people with diabetes, and in aging people generally. And so on.

The risk-factor-targeting drugs that have come out of this strategy have undeniably been successful in delaying the early appearance of some of the diseases of aging. But because these drugs rely on forcing metabolism to veer from its preferred course, they necessarily cause side-effects, such as the bleeding risk caused by the anti-clotting properties of aspirin, or the muscle and liver damage caused when statins restrict the production of life-giving metabolites that are produced in the same biochemical pathway as cholesterol. Moreover, while these medicines slow the rate at which particular forms of aging damage accumulate, they are powerless to stop them from continuing to build up in our tissues, because that would require completely shutting down the metabolic processes that they target — and those processes are essential to life itself.

But a better way is just over the horizon.

From Damage to Repair
As we've said before, there are many different things that can contribute to the total burden of aging damage in our bodies, including our genes, our lifestyles, and things in our environment. Genes, the conditions in the womb, nutrition, lack of exercise, pollution ... with all of the many factors that influence the onset of age-related disease, plus the side-effects of the very metabolic processes that give us life, you might think that completely preventing or curing those diseases would be a hopelessly complicated task. And indeed it would be, if your strategy were to try to hold back each and every one of those multiple causes of damage.

But actually, what all of this complexity reveals is the underlying simplicity of age-related diseases. Because while list of things that hasten the pace of age-related disease is long, they all contribute to the diseases of aging through the same critical intersection: each of them contributes damage to the cellular and molecular structures of our organs and tissues.

This suggests a new way to prevent and cure the diseases and disabilities of aging. Instead of fighting a hopeless battle to hold back all of the multiple, relentless metabolic forces that damage the cellular and molecular machinery of our bodies, what if we could repair the damage itself — even after it had already happened, and no matter what had caused the damage in the first place? Remember: the diseases and disabilities of aging are nothing more or less than the dysfunction that happens in our tissues when they accumulate too much of this damage to carry on their normal, youthful function. If we could remove, repair, replace, and render harmless the cellular and molecular damage that renders our living systems dysfunctional, then we could actually restore aging organs and tissues to youthful health and functionality, making them better and healthier than they were when we started treatment. The power of such an approach is that it would not merely delay the inevitable appearance of age-related disease: if it were done with zeal, and applied to the full range of the damage of aging, it would maintain our health and hold off the diseases of aging indefinitely.

There's a name for this exciting new field biomedical science: regenerative medicine. You've probably heard the term most often in the context of repairing and replacing a particular subset of the damage of aging: using living materials built in the laboratory to replace whole cells, tissues, and organs damaged by aging. But the damage of aging extends beyond the loss of the cells themselves: it extends to damaged molecules that accumulate on cells, and within cells, and in the non-cellular structures (like bones and ligaments) that support our organs and give them something to push against. And so, the methods of regenerative medicine need to be applied across the entire sweep of damage that drives age-related disease, on all scales. This systematic application of regenerative medicine to all of the damage of aging is what we've termed rejuvenation biotechnology.

From Theory to Application
How would this work in practice? Let's consider two particular kinds of aging that happen in the arteries: atherosclerosis — the accumulation of fatty plaques in our arteries — and the stiffening of those arteries, which leads to a progressive rise in blood pressure.

As we mentioned earlier, atherosclerosis begins when toxic byproducts of the cholesterol in our blood become trapped in the artery wall. Specialized cells called macrophages come in to clean up the mess: they engulf the cholesterol byproducts, which they then send to their cellular "recycling centers" (called lysosomes), where wastes are broken down into useful materials that can then be reused by the body. But even the lysosome has a limited capacity to clean up and detoxify these toxic cholesterol byproducts, and some of them (such as 7-ketocholesterol) can severely gum up the lysosome's works. Eventually, macrophages become bloated and necrotic, and immobilized in the artery wall, like so many rusting old beaters left out on the lawn to decay.

The buildup of these dead and dying cholesterol-laden macrophages is the necrotic core of atherosclerotic plaques that line our arteries as we age. Some people feel the building of the atherosclerotic plaque as it chokes off their blood vessels, in the form of spasming pain in their chests (angina) or their legs (claudication), along with nausea and pallor when they try to exercise or to exert themselves. But in many cases there are no obvious symptoms prior to the day that the unstable mess in their arteries erupts, throwing off a killer clot that rushes down the artery and becomes lodged in a blood vessel feeding the heart (causing a heart attack) or the brain (causing a stroke).

Statin drugs, as we mentioned, can slow the progression of atherosclerosis down a bit, by lowering the amount of cholesterol circulating in the blood; so can a prudent diet. But this approach can only be taken so far: if cholesterol levels got too low, our cells would not be able to build their membranes, and we wouldn't be able to produce numerous essential hormones that use cholesterol as a building block. Instead, rejuvenation biotechnology would tackle this problem by targeting the thing that actually damages our arteries: not cholesterol, but the toxic cholesterol byproducts that poison the macrophages that were sent in to clean them up.

The sticking point in clearing toxic cholesterol byproducts out of the arteries is the limited ability of the macrophages' lysosomes to break them down into reusable materials. So the solution to the whole problem of toxic cholesterol byproducts is to fortify those lysosomes with the enzymes that other organisms use to break these same substances down. SENS Research Foundation is funding research at Rice University to identify such therapeutic enzymes and deliver them to the lysosomes, and the team there has recently made a major advance toward the first regenerative therapy for atherosclerosis.

The stiffening of our arteries with age is a different process of arterial aging: although occurring in the same organs, it is caused by different kinds of damage to the arteries, and contributes to heart attacks and strokes in a different way. Bringing the methods of regenerative medicine to bear on the problem requires bringing the same principles to bear on the specific kind of damage underlying this quite different problem.

Arterial stiffening starts with blood sugar, which our arteries carry to our cells as a needed fuel, but which is also a chemically reactive substance. Just as the heat of a saucepan can quickly turn sugar crystals into sticky caramel or crispy-melty crust on a cake, so the lower temperatures in the body can more slowly trigger the sugar in our blood to form sticky bonds with proteins in the very arteries that carry it to our cells, causing those proteins to stick together. The ensuing "handcuffing" of the structural proteins in our arteries prevents them from flexing apart as they need to do, in order to accommodate the surge in the blood that happens with every pump of the heart muscle. As time goes on, more and more proteins get "handcuffed" into so-called crosslinks; the arteries become progressively less flexible, and the systolic blood pressure (the top half of the blood pressure cuff reading, which reflects what happens when the heart contracts) gets higher with age.

High blood pressure, notoriously, is a "silent killer," rarely having any symptoms of its own until they manifest in the problems it causes to other organs. The spiking jumps in systolic pressure can make the small blood vessels that feed the brain burst, just as a brittle old pipe can burst under high water pressure. It can injure the arterial wall, making it more vulnerable to infiltration by cholesterol, accelerating the process of atherosclerosis, and also makes a given plaque more likely to rupture. And the rising load of pressure it has to push against can force the heart to swell in size to meet the demand, which is ultimately self-defeating: the maladaptive swelling of the heart stiffens the organ as a whole, and makes it less able to take in the very blood it needs to distribute back to the heart and the rest of the body, setting you up for heart failure.

Again, you can only go so far by pushing blood sugar levels down (via diet or drugs), since blood sugar is an essential fuel. Instead, rejuvenation biotechnology zeroes in on the damage blood sugar causes in the arteries: the crosslinks themselves, not the precious fuels that cause them. Crosslinks are chemical structures, and like all chemical bonds, they can be broken. Medicines have been designed that bond to crosslinks in a precise way and break them apart, freeing the bonded structural proteins and allowing them once again to move apart and flexibly accommodate the force of the pulse when the heart beats. Already, prototype crosslink-breaking drugs have proven that this can be done in nonhuman primates and other animals, and now SENS Research Foundation has established a new crosslink-breaker research center in partnership with the Cambridge University Institute of Biotechnology to develop second-generation crosslink breakers for human use.

Research Toward a Reimagined Aging
By applying these rejuvenation biotechnologies to the damage that robs our arteries of their youthful integrity, we can restore them to health, and prevent the heart attacks, strokes, angina, and other suffering that flow from these diseases of aging. But remember, these are just two examples. It is SENS Research Foundation's mission to bring regenerative medicine solutions to all the diseases and disabilities of aging.

Could we really do this? Could medical science really develop a new class of medicines that would hold off the diseases of aging indefinitely, precisely by keeping our cells and tissues young — right down to the level of their constituent cells and biomolecules? Amazingly, the answer appears to be yes. To maintain and restore the molecular fidelity of youth in all of our cells and tissues requires only that we understand what the damage of aging is, and that we have a foreseeable way to repair it. As we've laid out elsewhere on our website, for the first time in the history of medical research, biomedical science has achieved these two preconditions, meaning that the path toward rejuvenation biotechnology is now open. Rejuvenation biotechnology is not available in doctors' offices today, but studies in animals and cells, and emerging capacities in biomedical research, clearly show biomedical researchers the way to apply regenerative medicine to each of the many kinds of aging damage that accumulate in our bodies and drive the diseases of aging. At this unique moment, medical science stands clutching sketched-out plans for the repair of the damage of aging — plans for a mighty siege-engine, to tear down the walls of aging and age-related disease.

At SENS Research Foundation, it is our mission to end the diseases and disabilities of aging by catalyzing this transformation. To make it happen, we are performing and funding critical-path rejuvenation research. We are building the alliance of aging patients, caregivers, and scientists demanding the new regenerative medicines. We are training up a new generation of biomedical researchers in the methods of rejuvenation research. SENS Research Foundation is pushing hard on every accelerator pedal that will hasten the emergence of rejuvenation biotechnology and as the medicine of the twenty-first century. Join us, and help make this reimagined aging a reality.