The real issue, surely, was not which metabolic processes cause aging damage in the body, but the damage itself. Forty-year-olds have fewer healthy years to look forward to than twenty-year-olds because of differences in their molecular and cellular composition, not because of the mechanisms that gave rise to those differences. (Location 80)
There are mutations in our chromosomes, of course, which cause cancer. There is glycation, the warping of proteins by glucose. There are the various kinds of junk that accumulate outside the cell (“extracellular aggregates”): beta-amyloid, the lesser-known transthyretin, and possibly other substances of the same general sort. There is also the unwholesome goo that builds up within the cell (“intracellular aggregates”), such as lipofuscin. There’s cellular senescence, the “aging” of individual cells, which puts them into a state of arrested growth and causes them to produce chemical signals dangerous to their (Location 84)
And of course, there are mitochondrial mutations, which seem to disrupt cellular biochemistry by increasing oxidative stress. I had for a few years felt optimistic that scientists could solve this problem by copying mitochondrial DNA from its vulnerable spot at “ground zero,” within the free-radical generating mitochondria, into the bomb shelter of the cell nucleus, where damage to DNA is vastly rarer. (Location 89)
years. For decades, my colleagues and I had been earnestly investigating aging in the same way that historians might “investigate” World War I: as an almost hopelessly complex historical tragedy about which everyone could theorize and argue, but about which nothing could fundamentally be done. (Location 112)
To design therapies, all you have to understand is aging damage itself: the molecular and cellular lesions that impair the structure and function of the body’s tissues. Once I realized that simple truth, it became clear that we are far closer to real solutions to treating aging as a biomedical problem, amenable to therapy and healing, than it might otherwise seem. (Location 118)
Aging has held us in a psychological stranglehold ever since we realized it existed, and that stranglehold remains intact to this day. I discussed in Chapter 2 the effect that this has on our willingness to think rationally about how terrible a thing aging is, and I explained why this irrationality used to have a valid psychological basis while there was no hope of combating aging, and also why it is now such a formidable obstacle. (Location 298)
Through the 1950s, ’60s, and ’70s, while gerontology was making its big push for recognition as a legitimate biological discipline, rhetoric developed to the effect that the infirmities of aging should be viewed as separable into two distinct phenomena: on the one hand, age-related diseases, and on the other hand, “aging itself.” (Location 337)
The motivation for this distinction, on the other hand, was purely pragmatic: by ring-fencing their area of work intellectually, gerontologists hoped to ring-fence it financially, too. (Location 340)
The fact that a fair proportion of people die of natural causes, rather than of any specific disease, might at first sight imply that aging is a process independent of diseases: something that increases people’s vulnerability to disease (thus making diseases more common among the elderly) but that also kills us itself if no disease does so first. This is only partly correct. (Location 357)
Take cancer, for example. A few types of cancer affect young people, but most types are never seen in people below the age of forty or so (except for people with very rare congenital DNA repair deficiencies). Some cancers are caused by viral infections—the best known of these is cervical cancer, caused by the human papilloma virus. (Location 362)
The first is that aging proceeds so much more slowly than specific diseases. So slowly, in fact, that we hardly notice its progression, whereas we are much more keenly aware of the more rapid development of conditions like cancer or diabetes. (Location 370)
Let me stress that I’m not saying the task is easy. The body is a great deal more complicated than any man-made machine—and what’s more, we didn’t design it, so we have to reverse-engineer its workings in order to understand it well enough to keep it running. (Location 427)
I’ve explained, earlier in this chapter, that there are no genes for aging in most species, simply because genes only survive if they confer enough benefit (and thereby enjoy enough selective pressure for their survival) to outweigh the constant stream of random mutations that all genes experience over evolutionary time, and a gene can’t confer any benefit if it only mediates a process that would happen anyway. (Location 508)
What we most certainly do have genes for, by contrast, is the panoply of interacting processes that turns each of us from a single cell into a fertile adult and that maintain our vigor and fertility until an age at which (in the wild) we’re very likely to have succumbed to starvation, predation, and so on. (Location 514)
So now: What does this have to do with calorie restriction, dauers, and the related genetic manipulations that I surveyed earlier in this chapter? Well, it’s actually very simple. In a famine, there are two big problems with passing on your genes. (Location 527)
Thus, famine shifts the happy medium toward favoring a more painstaking development process. And since famines are unpredictable events, occurring at irregular intervals, it’s not possible for evolution to determine a species’ ideal degree of perfectionism in advance: each individual organism must have the ability to respond to its situation. (Location 537)
First, the degree of life extension that has been obtained thus far in various species exhibits a disheartening pattern: it works much better in shorter-lived species than in longer-lived ones. Nematodes, as I mentioned above, can live several times as long as normal if starved at the right point in their development; so can fruit flies. (Location 547)
Second, the adjustment of metabolism that organisms undergo when food is scarce causes only a slowdown in the accumulation of molecular and cellular damage, not a repair of damage that already happened. (Location 553)
The other answer is the problem: most people leave the serious maintenance of their car until it’s too late. It’s obvious that the more damage a machine sustains, the more work is needed to rectify that damage; but more than that, the technology needed to rectify it becomes more and more sophisticated. (Location 615)
The answer, when you think about it, is simple: To fix a problem that already exists, you don’t need to know how it arose. A car mechanic replacing a car component doesn’t need to know what type of corrosion wore through a fuel line, or what size rock hit a windscreen; similarly, the geriatrician doesn’t need to know anything about free radical chemistry or cholesterol metabolism in order to treat cardiovascular disease or diabetes. (Location 629)
I had come to the conclusion that, in the best case, my mitochondrial gene therapy proposal might (and I emphasize might) also slow the rate of aging in humans attributable to most other causes by about 50 percent. (Location 650)
This process of dynamic metabolic adjustment is seen in the aging process, in fact. There are a number of aging changes that, while they might have some pathological consequences, are not themselves forms of damage. Putting it another way: they do not actually accumulate in the body’s cells and tissues; rather, they reprsent a shift in the equilibrium between creation and destruction of the molecules involved. (Location 682)
And, come to think of it, there seemed to me to be far fewer kinds of damage than processes that cause damage—hosts of different mutagens and “pre-mutagenic” changes to DNA, for example, but only two types of mutations: chromosomal and mitochondrial. Well, I mused, that’s a thought—just how many kinds of aging damage ARE there? And are there similarly promising fixes for the rest of them? (Location 692)
Trying to reduce free radical production was a job that many of my colleagues considered to be the best way to slow down aging damage, but (for the reason just given) actually pulling it off without seriously impairing the organism’s ability to carry on with life’s many duties would be extremely tricky. (Location 725)
There is glycation, the warping of proteins by glucose. Well, that seemed relatively easy, because it was well known in the field that a biotech startup called Alteon was already running clinical trials using a compound called ALT-711, which appeared to reverse the protein cross-linking that this process caused. (Location 741)
diabetics. It was proof-of-principle that without interfering with glucose metabolism, you could allow the formation of protein cross-links but prevent the pathological results by undoing the damage after the fact. (This is an important and common theme, as you will see—don’t interfere with the process, but rather repair or clean up the damage that has accumulated.) (Location 745)
What else? There are the various kinds of junk that accumulate outside the cell: beta-amyloid, the lesser-known transthyretin, and possibly other substances of the same general sort. Here again, recent studies in the private sector—this time by a Californian company named Elan—had shown that you could actively remove the problem, in this case by vaccinating mice against the amyloid plaque and letting their immune cells gobble the stuff up. (Location 749)
We must also address the unwholesome goo that builds up within the cell, such as lipofuscin. I started to get quite excited at this point, because just a year previously, in Dresden in June 1999, I’d come up with a new proposal to eliminate such material, involving the identification and engineering of enzymes from soil bacteria. (Location 753)
Another item that must be added to the list is cellular senescence, the “aging” of individual cells. Senescence, in this meaning of the word, is a state of arrested growth in which the cell produces chemical signals dangerous to their neighbors. (Location 761)
There’s also the depletion of cells—of nondividing cells like neurons or heart cells, which are not naturally replaced when they die, and also the more paradoxical depletion of stem cell pools essential to healing and maintenance of tissue. (Location 767)
At root, I was addressing a simple question: if geriatrics fails because prevention is better than cure, and gerontology fails because our understanding of metabolism is so limited, then might an intermediate target be the best of both worlds? Might it be possible to repair damage after it’s been laid down (hence avoiding the need to understand the details of how it’s laid down) but before it spirals out of control (hence also avoiding the losing battle that is geriatrics)? (Location 782)
Almost everyone has heard of free radicals by now. Their involvement in aging is asserted so often and so confidently in popular press articles—especially articles trying to promote the latest “antioxidant” nutritional supplement—that you’d think the matter was done and dusted. (Location 871)
Free radicals in biology are, for the most part,1 oxygen-based molecules that are missing one of the electrons in their normal complement. (Location 875)
Some unusual molecules—antioxidants—finesse this logic and are relatively stable even when they contain an unpaired electron. These molecules can “quench” free radical chain reactions. (Location 883)
Using a series of preliminary biochemical reactions (each of which generates a small amount of energy), energy from food in the form of electrons is transferred to a carrier molecule called NAD+ (and a similar one called FAD). (Location 899)
Unlike hydroelectric dams, however, the use of chemical energy in food to generate ATP via this system is a chemical reaction. As with the burning of coal or wood to release energy, the powering-up of ADP into ATP consumes oxygen, which is why we have to breathe to keep the whole system running: oxygen is the final resting place of all those electrons that are released from food and channelled through the proton-pumping electron transport chain. Thus, the whole cycle is called oxidative phosphorylation (OXPHOS). (Location 911)
Once scientists established that mitochondria were the main source of free radicals in the body, it was quite quickly realized that these organelles would also be their main target. (Location 923)
What’s that, you say? Well, whereas other components of the cell have all their proteins coded for them by the cell’s centralized genetic repository in the nucleus, mitochondria have their own DNA for thirteen of the proton-pumping, ATP-generating (Location 928)
If that DNA is significantly damaged, the mitochondrial machinery will go awry. Unfortunately, it’s clear that mitochondrial DNA does suffer a lot of self-inflicted damage, taking as much as a hundredfold more initial oxidative “hits” than the cell’s central, nuclear DNA, and suffering many times more actual, enduring mutations with age. (Location 930)
mitochondrial catalase for humans? Well, in part (Location 1413)
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more and more room in the lysosomes (Location 1957)
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dissolved in the fluid bathing the cells of the brain rather than precipitating out (Location 2745)
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