Q: Because the cellular and molecular damage of aging is a by-product of metabolism, I have always assumed that it accumulates throughout our entire lives – from when we are a baby until we die. Is this true? Is there any research showing that very young children have low levels of tissue-stiffening crosslinks, extracellular aggregates like beta-amyloid, or intracellular aggregates (like lipofuscin or the ones driving atherosclerosis) in their tissues?
A: Scientists don’t have any single, comprehensive answer to this broad question, in part because there hasn’t been a systematic investigation into it, and in part because the answer likely depends on the specific kind of aging damage under consideration. To really answer it, one would need to begin an investigation for each aging-damage precursor by taking tissue samples from newborns, and then performing ongoing testing periodically throughout life. As a second-best, you’d do a cross-sectional study comparing neonates, five-year-olds, pubescent children, very young adults, and then adults, including ages spread fairly evenly across the remaining lifespan. It would be difficult to perform such studies both institutionally and technically, as they would be quite expensive and would involve sourcing tissue samples from individuals of all of these ages, acquiring consent to use them for studies, and securing funding to do all this. Some of the tissues would have to be from living donors, or the most immediately deceased, leading to reluctance to donate because of invasiveness or sensitivity around the dead. Obtaining approval to test neonates and very young children would be challenging due to these individuals’ inability to consent, plus reluctance by parents to give it; moreover, it might be hard to justify collecting them from subjects whose risk as related to aging damage is many decades into the future.
From a technical standpoint, it is already difficult to quantitate many kinds of aging damage even in older people. The extreme case here is the key tissue-stiffening crosslink glucosepane, which is very fragile when subjected to most laboratory tissue treatments and has heretofore needed to be painstakingly extracted from tissues using a laborious series of sequential enzymatic extractions. Happily, this is likely to change soon, thanks to excellent progress being made in research that SENS Research Foundation has been funding in the Spiegel Research Group at Yale for several years now, developing enabling technologies for the development of glucosepane crosslink breakers. We are pleased to be able to report that this research has reached an important milestone: the first-ever laboratory synthesis of glucosepane. By incorporating these synthetic glucosepane structures into peptides, it should be possible to develop highly specific antibodies that will conveniently identify glucosepane crosslinks in tissue samples. (Meanwhile, the Spiegel group is going on to work on the biologically-significant isomers of glucosepane). And it is inherently even more difficult to probe tissue samples for aging damage in very young people, for the obvious reason that the damage is by definition present at much lower levels in very young people’s tissues than it is in older people’s.
What little data we do have on aging damage precursors in the very young comes, for instance, from autopsy studies of stillborn infants. All such infants have at least some lipid deposition in their arteries, with as many as 25% of them having the “fatty streaks” that are the first visible sign of accumulating foam cells. These early lesions are particularly common in infants born to mothers with high serum cholesterol. Children are also born with some mechanical fatigue and fraying of the complex, lamellar structures of the stretchy protein elastin that provide arterial tissue with its elasticity, and this damage progressively increases with age. And there is already crosslink damage in the trachea and the bronchi of the lungs of newborn rats.
However, the situation is not clear with beta-amyloid, the sticky protein at the core of Alzheimer’s disease and that also contributes to other dementias of aging and to “normal” age-related cognitive decline. Insoluble deposits (plaques) of beta-amyloid are visible in the brains of deceased Alzheimer’s patients and many older people who are not yet demented, but plaques don’t appear in the brains of most people until they are in late middle age, even if they ultimately go on to develop Alzheimer’s.
But beta-amyloid doesn’t just appear out of nowhere the day it begins forming deposits in the brain. Beta-amyloid also aggregates into smaller and more soluble forms called oligomers that remain dissolved in the cerebrospinal fluid (CSF) bathing the brain and spinal cord, and these are generally agreed to be at least as harmful. Soluble beta-amyloid is present in the brain and at much younger ages, and indeed the level of oligomers in a person’s spinal CSF begins to fall about 10-15 years before plaques appear in their brain. This appears to be due either to a failing ability of the brain to transport soluble beta-amyloid out of itself and across the protective blood-brain barrier, or because plaques are beginning to imperceptibly “seed” in the brain and are drawing soluble beta-amyloid into themselves out of the CSF, thereby lowering its CSF concentration.
Beta-amyloid levels in CSF and plasma seem to be stable for the first few decades of life, which may mean that the body is still able to metabolize it away or excrete it through the bile, or that other subtler changes are occurring. The latter is suggested by abnormalities seen in the brains and circulations of young people carrying the disease-associated ε4 form of the gene for the lipid transport protein ApoE. Carriers of this ApoE variant are at substantially higher risk of developing Alzheimer’s within the course of their lifetime, and accordingly they suffer an earlier fall in CSF beta-amyloid and an earlier appearance of plaques. But even before a change in CSF beta-amyloid occurs, there is evidence of increased oxidative stress and impaired ability to use glucose as a fuel in their brains, so some other Alzheimer’s-related change is already underway that may involve beta-amyloid metabolism.
It’s important to remember, however, that from the perspective of developing the therapies we need to delay and prevent degenerative aging, it doesn’t matter whether or how much of these various aging lesions are present in very young people. Whatever their level may be, and whatever their rate and mechanisms of accumulation, the aging damage that is already present in the bodies of young adults is clearly harmless at the low levels at which it’s present, as evidenced by the (by definition) youthful good health that college students and thirtysomethings enjoy.
It’s only decades later, as the level of cellular and molecular damage in different tissues accumulates to a characteristic “threshold of pathology,” that enough of a given tissue’s functional units are disabled to overcome its evolutionarily-inbuilt redundance and meaningfully impair tissue function. Even when some function has been lost, the effects on health may be subtle at first — more of an annoyance than something most people would regard as a serious medical problem. For instance, some people in who are late in the middle of their current life expectancies develop low levels of alpha-synuclein aggregates in the nerves controlling the motion of their GI tracts and the regulation of their heartbeats. These people develop symptoms that may include slight delays in adjusting their heart rates to changes in activity levels, or troubles with their digestion and elimination systems, but nothing likely to send them rushing to their doctors in search of treatment. It’s only later, once the alpha-synuclein pathology spreads across their brains, that the damage finally gets severe and tissue-specific enough to cause the more severe symptoms that are diagnosable as part of Parkinson’s disease.
In order to restore and maintain youthful health and functionality, then, we don’t need to eradicate aging damage from the tissues of aging people; nor do we need to begin treating healthy young adults to push their burden of aging damage down to levels typical of children. Rather, we only need to develop rejuvenation biotechnologies capable of periodically removing, repairing, replacing, or rendering harmless enough of a tissue’s molecular and cellular damage as to restore its structural integrity to what it is in young adults — complete with its original, lower but nonzero level of damage. At that point, the rejuvenated body will be structurally and functionally young, and its metabolic derangements will be restored to health as a downstream consequence of the intrinsic order of the youthful body. With this return to normal functionality at every level will come restored health, vigor, and vitality that ongoing periodic treatment can maintain — for many years longer at first, and ultimately indefinitely.
