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https://www.economist.com/node/21536539
Ageing
Forever young?
A way to counteract part of the process of growing old
Nov 5th 2011
BIOLOGISTS have made a lot of progress in understanding ageing. They have not, however, been able to do much about slowing it down. Particular versions of certain genes have been shown to prolong life, but that is no help to those who do not have them. A piece of work reported in this week's Nature by Darren Baker of the Mayo Clinic, in Minnesota, though, describes an extraordinary result that points to a way the process might be ameliorated. Dr Baker has shown—in mice, at least—that ageing body cells not only suffer themselves, but also have adverse effects on otherwise healthy cells around them. More significantly, he has shown that if such ageing cells are selectively destroyed, these adverse effects go away.
第二个问题是说，以下哪种行为和实验中的行为（实验就是喂这些mice药，杀死任何产生P16的细胞）延缓衰老的效果是相似的？狗主选的“提高能够产生P16的细胞分裂的upper limit，并且保持不能产生P16的细胞分裂的upper limit不变”，但是不确定。
The Hayflick limit, as the upper bound is known (after Leonard Hayflick, the biologist who discovered it), is believed to be an anticancer mechanism. It provides a backstop that prevents a runaway cell line from reproducing indefinitely, and thus becoming a tumour. The limit varies from species to species—in humans, it is about 60 divisions—and its size is correlated with the lifespan of the animal concerned. Hayflick-limited cells thus accumulate as an animal ages, and many biologists believe they are one of the things which control maximum lifespan. Dr Baker's experiment suggests this is correct.
Age shall not weary them
Dr Baker genetically engineered a group of mice that were already quite unusual. They had a condition called progeria, meaning that they aged much more rapidly than normal mice. (A few unfortunate humans suffer from a similar condition.) The extra tweak he added to the DNA of these mice was a way of killing cells that produce P16INK4A. He did this by inserting into the animals' DNA, near the gene for P16INK4A, a second gene that was, because of this proximity, controlled by the same genetic switch. This second gene, activated whenever the gene for P16INK4A was active, produced a protein that was harmless in itself, but which could be made deadly by the presence of a particular drug. Giving a mouse this drug, then, would kill cells which had reached their Hayflick limits while leaving other cells untouched. Dr Baker raised his mice, administered the drug, and watched.
第二段 科学家做基因改造的老鼠实验，3天注射一次杀死分泌P16细胞的药，发现肌肉组织衰老速度变得缓慢了，但是心脏却没有，因为没有分泌P16的细胞。
The results were spectacular. Mice given the drug every three days from birth suffered far less age-related body-wasting than those which were not. They lost less fatty tissue. Their muscles remained plump (and effective, too, according to treadmill tests). And they did not suffer cataracts of the eye. They did, though, continue to experience age-related problems in tissues that do not produce P16INK4A as they get old. In particular, their hearts and blood vessels aged normally (or, rather, what passes for normally in mice with progeria). For that reason, since heart failure is the main cause of death in such mice, their lifespans were not extended.
The drug, Dr Baker found, produced some benefit even if it was administered to a mouse only later in life. Though it could not clear cataracts that had already formed, it partly reversed muscle-wasting and fatty-tissue loss. Such mice were thus healthier than their untreated confrères.
Analysis of tissue from mice killed during the course of the experiment showed that the drug was having its intended effect. Cells producing P16INK4A were killed and cleared away as they appeared. Dr Baker's results therefore support the previously untested hypothesis that not only do cells which are at the Hayflick limit stop working well themselves, they also have malign effects (presumably through chemicals they secrete) on their otherwise healthy neighbours.
Regardless of the biochemical details, the most intriguing thing Dr Baker's result provides is a new way of thinking about how to slow the process of ageing—and one that works with the grain of nature, rather than against it. Existing lines of inquiry into prolonging lifespan are based either on removing the Hayflick limit, which would have all sorts of untoward consequences, or suppressing production of the oxidative chemicals that are believed to cause much of the cellular damage which is bracketed together and labelled as senescence. But these chemicals are a by-product of the metabolic activity that powers the body. If 4 billion years of natural selection have not dealt with them it suggests that suppressing them may have worse consequences than not suppressing them.
By contrast, actually eliminating senescent cells may be a logical extension of the process of shutting them down (they certainly cannot cause cancer if they are dead), and thus may not have adverse consequences. It is not an elixir of life, for eventually the body will run out of cells, as more and more of them reach their Hayflick limits. But it could be a way of providing a healthier and more robust old age than people currently enjoy.
Genetically engineering people in the way that Dr Baker engineered his mice is obviously out of the question for the foreseeable future. But if some other means of clearing cells rich in P16INK4A from the body could be found, it might have the desired effect. The wasting and weakening of the tissues that accompanies senescence would be a thing of the past, and old age could then truly become ripe.
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发表于 2019-1-24 22:38:35
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