Which metabolic changes cause aging in humans?

The secret of aging : How do we stay young forever?

From the age of twenty, slurping three raw eggs a day - was that the trick that made Emma Martina Luigia Morano-Martinuzzi, born on November 29, 1899, live to be 117 years and 137 days in excellent health? Or was it the quiet, godly and independent life without a husband and children in the idyllic town of Verbania in Piedmont, Italy, which had brought about the record age of the woman, who then died on April 15, 2017?

You will probably never know for sure. Because there are indeed many ideas, tricks and remedies that are said to delay or even reverse the aging process. What they all have in common, however, is that there is still no evidence of effectiveness. Only the longest long-term study of all time could provide this: Thousands of people would have to commit themselves to swallowing eggs for decades, and just as many would have to forego eggs for control purposes. After about a hundred years it should be clear whether raw hen's eggs can really prolong human life.

Aging research is rather skeptical in this regard. But there is no lack of promising approaches. Because knowledge about aging processes, repair processes in the genetic material and the growth and death of cells in the aging body has increased rapidly. And tests that have already extended the life of worms, flies and mice are repeated here and there on humans.

The fountain of youth could be discovered by those researchers who are working on clearing out aged cells from the body (“cell void”). Others inject the elderly with the blood of young donors (“young blood”). And there are those who swear by active ingredients that are supposed to regulate the metabolism in such a way that the body does not or hardly ages - for example the red wine component resveratrol ("restrained metabolism").

Still others rely on reactivating the body's self-healing powers (“workshop against old age”). The latest hype, however, revolves around a tablet cocktail. It should help the body's defenses, which rapidly decline with age, to regain strength ("thymus cure"). The experiment is said to have worked to some extent with nine voluntary rejuvenation spa guests.

Young blood

It sounds like from the script of a third-rate Dracula film: blood is drawn from young people and injected into old people in order to rejuvenate the malady cells and organs. The idea goes back to a no less gruesome experiment by the age researcher CliveMcCay, who connected the bloodstream of young rats to older specimens in 1956 - a so-called "parabiosis". After 18 months, he found that the older ones had tapered bones in terms of density and weight. In the 1970s it turned out that old rodents with such young blood transfusions lived up to five months longer than animals that had not contracted parabiosis.

At the turn of the millennium, the stem cell researcher Amy Wagers, now at Harvard University, made use of this knowledge. She wanted to find out whether there are messenger substances in the body that signal the cells how often they should divide: frequently, as in youth, or less frequently, as in old age. She remembered the parabiosis experiments and in 2008 let blood of young mice flow through the veins of old animals.

In fact, she observed cell division activity in the muscles, brain and liver of the old animals as in the young. Even the previously shaggy fur shone again. Since then, Wagers has been looking for the messenger substances of the fountain of youth in the blood that signal the stem cells to resume their activity and reactivate repair processes.

One of them is oxytocin, previously known only as a hormone that induces labor at birth and promotes social bonds. The oxytocin content in the blood of mice decreases with increasing lifespan. When the researchers bring the oxytocin concentration back to youthful levels, the stem cells in the decrepit muscles wake up and form fresh muscle cells. Another signal is probably the growth factor Gdf11, which promotes muscle regeneration. But there is certainly much more.

The Alkahest company in Menlo Park, California, does not want to wait for the researchers to search. She has been giving Alzheimer's patients over 50 years of age regularly blood plasma transfusions from donors younger than 30 since 2014. The company's founder Tony Wyss-Corey, a full-time neurologist at Stanford University, had previously brought the brains of older mice up to speed with the blood plasma of young mice: new nerve cells were formed again and learning and memory performance improved. The Californian company Ambrosia has started a second “study”. Volunteers are allowed to volunteer as guinea pigs for a fee of only $ 8,000 and then have the blood of 16 to 25 year olds transferred.

Neither of these test series will be able to prove whether young blood can prolong people's lives. “That is a long way from solid science,” says Max Planck researcher Denzel. "At the moment the risk is higher than the benefit."

Because there are reasons why the body slows down its stem cells and thus its ability to repair with increasing age: to counteract the development of cancer. Therefore, it is at least daring to be administered large amounts of foreign blood as long as researchers do not understand which substances in it, in which combination and concentration and with which side effects are responsible for the rejuvenation effect proven in mice, but not humans.

At the beginning of the year, the US regulatory authorities even explicitly warned against these blood plasma infusions: They have "no proven clinical effect" and are risky. In any case, blood plasma should not be practicable as a comprehensive fountain of youth. The donor blood is hardly sufficient for operations.

The thymus cure

Middle-aged men take a special mixture and suddenly feel fit again, even long gray hair grows brown - what sounds like a fairground miracle, according to Gregory Fahy, head of research at the Californian company "Intervene Immune", has just happened: You have turned back the biological clock.

As part of the “TRIM” study, the researchers administered the growth hormone hGH in combination with the testosterone-like DHEA and the diabetes drug metformin to nine healthy men between the ages of 50 and 65 for twelve months. They determined rejuvenation based on three criteria: the composition of the immune cells in the blood, a DNA clock (see page 5) and the growth of the thymus, a gland behind the breastbone, of which they made magnetic resonance images. The thymus is responsible, especially in childhood and adolescence, for developing the body's defense system. Immune cells (T cells) mature there. "Stimulating the immune system via the thymus is an approach that could help against aging," says Martin Denzel, aging researcher at the Max Planck Institute in Cologne.

In the men examined, the organ regenerated after twelve months, says head of research Fahy. The blood composition now corresponds to that of young people. And on the DNA clock, the subjects were on average two and a half years younger. The results have not yet been published in a specialist journal.

Aging researcher Denzel thinks the study is "an exciting matter". However, one should not overinterpret the results. Nine men are very few, and there is no control group. The active ingredient hGH is also controversial. Some athletes take the hormone to dope themselves. "Of course that helps first to get fitter and stronger," says Denzel. However, previous studies on animals have shown that those who have little growth hormone tend to live longer. If this is also the case with humans, one could “use up one's resources by giving additional hormones, then in the long term one has not gained anything”.

Reins on the metabolism

Either there is food in abundance and the best conditions to bring the offspring through. Or it is barely enough for its own survival, let alone for the brood. Adjusting living beings to such extremes has been the task of "mTOR" for billions of years. This molecule boosts the metabolism of yeast cells as well as flies, worms, mice and humans when the environmental conditions are favorable. If there is a deficiency, it prescribes a fasting cure - which, as a "side effect", leads to a certain extension of life.

A drug called rapamycin, whose active ingredient originally comes from a soil bacterium from Easter Island Rapa Nui, has the same effect. Rapamycin blocks mTOR, so it sets the metabolism to "fasting" - and incidentally extends the life of many laboratory animals by around 25 percent.

Nobody knows yet whether it can also extend people's lives for this substance. Experiments with cells from patients with progeria create hope. With this rare hereditary disease, children already show signs of age at the age of two and usually die in their teenage years. mTOR is overactive in the rapidly aging cells of these children. If rapamycin is administered, i.e. if mTOR is inhibited, the aging process is delayed. And in mice with progeria, rapamycin even stops the muscle and nerve loss associated with the disease.

But testing the substance on people is risky: too many side effects, such as a greatly increased risk of infection. In a study of 18 patients, two became infected so severely that one died. An alternative could be metformin, the diabetes drug that has been approved for decades and has been prescribed millions of times. Of 78,000 diabetics, those who took metformin lived an average of 18 percent longer. The non-commercial American Federation for Aging Research, an association of aging researchers, is currently testing metformin in 3,000 people aged 70 to 80 for five to seven years.

The cell void

It seems obvious that those who are getting closer to death and aging are whose cells gradually die off. However, the death of cells does not normally cause any problems for a healthy organism, on the contrary: special suicide programs even deliberately drive defective or infected cells to their death - in order to send healthy replenishment from stem cells. The problem is rather those cells that are neither really alive nor dead.

These "undead", "senescent" cells get out of hand with age and send false signals to the immune system, causing false inflammatory reactions. Therefore, they are the target of a whole range of strategies that researchers are using to bring people closer to the fountain of youth.

At the Erasmus University in the Netherlands, for example, Peter de Keizer tries to destroy senescent cells in naturally and artificially accelerated aging mice with infusions of a certain peptide, a short protein.

In fact, the animals got a youthfully smooth coat again, lost their age-related frailty, soon ran twice as far as comparison mice that had not received the therapy and also got their youthful kidney function back. Apparently the peptide inhibits a molecule (Foxo4) that is found almost exclusively in zombie cells, where it blocks the switch for the suicide program. Keizer's peptide releases the brakes, the half-dead are allowed to step down and make room for new, young cells.

Workshop against aging

It’s not easy for cells. Even simple sunbathing causes damage to their genetic make-up. However, living things have been grappling with such adversities for ages and have developed repair mechanisms. But their effectiveness dwindles with age. This is due to the fact that the amount of the substance NAD + in the cells decreases in older mice and probably also in humans. If this nicotine amide dinucleotide is dripped into the drinking water of elderly mice, the repair function of the cells improves within weeks.

And their lifespan may also be extended. Because NAD + works closely with a protein: sirtuin. The role of this protein is not yet entirely clear. But if mice, worms or flies are put on a strict diet ("calorie restriction"), the sirtuin content in their cells increases and they live up to 50 percent longer.

Companies like L-Nutra in Los Angeles are already trying to capitalize on this: They sell tailor-made, near-zero diets for around $ 300 a week to fountain of youth believers. Research, on the other hand, is looking for substances that only fool the body into the life-prolonging starvation diet by influencing the human sirtuin or NAD +.

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