Excerpt from Why we die: The new science of aging and the quest for immortality Written by Venki Ramakrishnan with permission from William Morrow, Publisher, HarperCollins.Copyright © 2024 by Venki Ramakrishnan.
Lessons from a sneaky worm
We all know families of people who have lived long lives. But how exactly do genes influence lifespan? A study of 2,700 Danish twins found that the heritability of human longevity (the extent to which genetic differences influence differences in age at death) Quantitative measures indicating that this is only about 25%. Furthermore, these genetic factors were thought to be due to the sum of small effects from a large number of genes, making it difficult to pinpoint them precisely at the individual gene level. When the Danish study was conducted in his 1996, lower insects were already helping to overturn that idea.
That sneaky bug was a soil nematode. Caenorhabditis elegans, was introduced to modern biology by Sidney Brenner, a giant in the field known for his acerbic wit. Although he was born and received his first education in South Africa, he spent much of his productive life in Cambridge, England, and later joined the Brenner empire as he established laboratories around the world, from California to Singapore. Some say it never sank. He became famous for being the first to discover his mRNA. More generally, he worked closely with Francis Crick on the nature of the genetic code and how it is read to make proteins. Once Brenner and Crick have determined that they have solved the fundamental problem of using genetic information to make proteins, they have no idea how complex animals develop from a single cell and how the brain and its nervous system I turned my attention to investigating how it works.
Brenner was identified. C.Elegance They are easy to propagate, have a relatively short generation time, and are transparent, allowing the cells that make up the nematode to be visible, making them ideal organisms for research. He trained many scientists at his MRC Molecular Biology Laboratory in Cambridge and created an entire worldwide community of researchers to carry out his research. C.Elegance Everything from development to behavior. Among his colleagues was biologist John Sulston, whom we met in Chapter 5. One of Sulston’s more notable projects was to painstakingly trace the lineage of each of the approximately 900 cells of a mature C. elegans, starting with the first single cell. An unexpected discovery is that certain cells are programmed to die at precise stages of development. Scientists went on to identify the gene that causes these cells to commit suicide at the right time for the organism to develop.
For an animal with only 900 cells, this nematode is incredibly complex. They have some of the same organs as larger animals, but they have a simpler form: mouth, intestines, muscles, brain and nervous system. They have no circulatory or respiratory systems. Nematodes are small, only about 1 millimeter long, but when observed under a microscope, you can easily see them wriggling around. Since they are hermaphrodites, they produce both sperm and eggs. C.Elegance Asexual reproduction is also possible depending on the conditions. They are normally sociable, but scientists have discovered a mutation that makes them antisocial. Nematodes feed on bacteria and, like bacteria, are grown in Petri dishes in the laboratory. It can be frozen indefinitely in a small vial in liquid nitrogen and thawed and revived when needed.
Worms typically survive for several weeks. However, when faced with starvation, they may enter a state of dormancy called . dauer (Related to the German word meaning endurance) During this period they can stay alive for up to two months before re-emerging until nutrients are again abundant. Compared to the human lifespan, this corresponds to her 300 years. Somehow, these worms managed to halt the normal aging process. However, there are some caveats. Only larvae can enter the dauer state. Once the animal passes through adolescence and becomes an adult, this option disappears.
David Hirsch was interested in C.Elegance He was a research fellow under Brenner at the University of Cambridge, and continued his work on worms when he joined the faculty at the University of Colorado. So he took on a postdoctoral fellow named Michael Klass, who wanted to focus on aging.
This was a time when aging was simply considered a normal and inevitable process of wear and tear, and mainstream biologists had a degree of disdain for the study of aging. However, the situation was beginning to change as the US government became concerned about the aging of the population. As Hirsch recalled, the National Institutes of Health had just established the National Institute on Aging, and he and Klass were motivated, at least in part, to work in the field by the chance of receiving federal funding. Because I knew it was there.
Hirsch and Klass were the first to show that, by a number of criteria, C. elegans rarely, if ever, age in the dauer state. Next, Klass wanted to see if he could isolate mutants of the worm that lived longer but didn’t necessarily go into a dormant state. This could help identify genes that influence lifespan. To quickly generate mutants that could be screened for longevity, he treated worms with mutagenic chemicals. He eventually obtained thousands of nematode plates and continued his research after establishing his own laboratory in Texas. In 1983, Klass published several papers on long-lived mutant nematodes, but eventually closed his lab and joined Abbott Laboratories near Chicago. But before doing so, he sent a frozen batch of mutant worms to his former colleague from Colorado, Tom Johnson. Tom Johnson was enrolled at the University of California, Irvine by then.
Johnson found that by inbreeding several mutant worms, their average lifespans varied from 10 to 31 days, suggesting that, at least in worms, lifespan has a significant genetic component. I inferred that he was involved. It was not yet clear how many genes affected longevity, but in 1988 Johnson, working with an enthusiastic undergraduate named David Friedman, discovered that many genes each made a small contribution to longevity. influenced. Instead, a single gene mutation they called age-1 was found to increase lifespan. Johnson went on to show that while worms with the one-year-old mutation had lower mortality rates at all ages, their maximum lifespan was more than twice that of normal worms. Because life expectancy can be influenced by all kinds of factors not necessarily related to aging, maximum life expectancy, defined as the lifespan of the top 10 percent of the population, may be a better measure of the effects of aging. It is believed that there is. such as environmental hazards and disease resistance.
