What Causes Alzheimer’s Disease?
Other diseases claim limbs or organs; Alzheimer’s devours the self, making it one of the few afflictions widely regarded as being worse than death. And it is on the rise. The progressive, degenerative brain disorder afflicts an estimated 4 million Americans and could strike 14 million by 2050. Memory and thinking go first; eventually, loss of brain function causes death.
Many researchers believe that the culprit is a surfeit of specialized enzymes that split off too much of a protein called amyloid beta peptide. These fibrous peptides glom on to healthy neurons to form amyloid plaque, making them weaken and die. The tendency to crank out the enzymes in excess is most likely genetic, which may be why Alzheimer’s tends to run in families.
Drug companies are vigorously seeking chemicals to block the enzymes, but whether that is the best therapeutic route is by no means certain. “Everybody is gung ho on this amyloid hypothesis, but it’s still just a hypothesis,” says Franz Hefti, an Alzheimer’s researcher and executive vice president for development at Rinat Neuroscience Corporation, a biotechnology company specializing in neurological-disorder drugs. “It could be part of the disease process, or it could be a sort of sideshow of the disease process.” A competing theory, Hefti says, holds that the growth of neuritic “tangles,” linked to specific proteins called tau proteins, is the primary cause, with the wayward peptide-splitting enzymes simply an offshoot.
“These are big questions, and the pharmaceutical industry is literally spending billions to get at the answers,” says Hefti. From the perspective of baby boomers slouching toward 65—about the age when the most common form of Alzheimer’s starts to manifest—it is money well spent.
Can Aging Be Arrested?
Aging is the ultimate disease—everyone is born with it, and the survival rate is zero. Lifestyle changes can modify life span, but genes appear to set the upper limit. “It is gene expression that allows our bodies to undergo what we think of on a wholesale level as aging,” says Michael Fossel, editor of the Journal of Anti-Aging Medicine. Good genes no doubt explain why, despite smoking cigarettes for some 90 years, Frenchwoman Jeanne Louise Calment died in 1997 at 122 years of age, the longest life span yet recorded.
So can this limit be challenged? Instead of stretching life span within the framework of biomechanical aging, will we break the frame itself? “Can we arrest aging now? No,” says Fossel. “Do we have good reasons to think it can be arrested? Yes.” Fossel believes the first viable antiaging therapy will target telomeres, which are repeating DNA sequences at the ends of chromosomes. Each time a cell divides, some of the telomere is lost. When the telomere becomes too short, the cell can no longer function and dies. An enzyme called telomerase can elongate chromosomes after each division, theoretically making a cell immortal, but only fetal tissues, adult germ cells, and tumor cells use telomerase—in normal body cells, the stuff is virtually undetectable. “I think the most effective point of intervention will turn out to be telomerase,” says Fossel. By manipulating it, he says, “we can now show that you can prevent, or even reverse, aging with individual cells in vitro.”
Using the enzyme to slow aging in a whole human body will be tricky, he concedes. “Whenever you want to intervene in medicine, you have to ask yourself: Why did nature do it that way in the first place?” Fossel says the most likely reason for our cells’ finite life span is preventing “wholesale, unrestricted growth”—in other words, malignancy.
Another possible antiaging gambit may involve copying 13 specific genes from a cell’s mitochondria and transplanting them into the nucleus, where they would be protected from free-radical damage. “That’s a major undertaking,” Fossel admits. “That makes fooling with telomerase look like child’s play.”
So what, realistically, is the outlook? “It’s possible that 100 years from now, people could look back and say we really haven’t made any progress at all,” he says. “But my bet is that we will look back and say, ‘Right around 2005 or so, that’s about when we started to really alter the aging process.’”
Can Humans Learn to Regenerate?
Chop off a starfish’s arm or a salamander’s tail and the doughty little creature will promptly start growing a new one. A wounded zebra fish can regrow almost anything it loses, including skin, bone, joints, nerves, arteries, veins, muscle, eyes, spinal cord, and heart.
Human beings, however, have limited regenerative powers, which is bad news on several fronts. Not only is a severed arm lost forever, but the inability to regenerate robustly is the underlying cause of many cardiovascular and neurological disorders. A wide variety of conditions that affect human adults, with the notable exception of cancer and infections, could be aided if we could stimulate regeneration, argues Mark T. Keating, a professor of cell biology at Harvard Medical School.
“Actually, humans can regenerate to some extent,” he says. “We can regenerate skin and blood and the tips of digits, and we can regenerate the liver big time—you can remove half of a liver and it grows back.” Keating thinks we may have evolved this way because primitive humans suffered cuts and scrapes and damaged their livers eating questionable foods. “There was a great survival advantage to regenerating these elements,” he says, that was worth the metabolic cost.
Today’s maimed or paralyzed human beings would happily convalesce in bed for a few months to regrow lost parts if it were possible. The key to stimulating regeneration, Keating believes, will be inducing cells to undo their differentiation, the process by which a single cell becomes hundreds of distinct tissues such as muscle, blood, bones, and brain. Organisms like zebra fish readily dedifferentiate cells near the injury, undergoing a cellular age regression in which “they form something like stem cells, although they are not quite the same as stem cells,” says Keating. “Those cells are the source. They give rise to the daughter cells that the organism needs.”
Just what triggers the cells surrounding a zebra fish’s injury to start dedifferentiating is unknown, but Keating says regenerative therapy for human beings will in some circumstances involve transplanting stem cells to the injured area. “There are also molecular therapies. There’s already a drug called Epogen that increases the formation of red blood cells by your own stem cells,” he says. Keating guesses that an effective medicine that induces some degree of regeneration “will happen in 15 to 20 years, perhaps.” Regenerative medicine, he says, is a “cool, growing field. I am positive that a therapy will happen, but I’m not positive how long it will take.”