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Tithonus and the Fruit Fly: New Science and Old Myths

2008; Wiley; Volume: 22; Issue: 6 Linguagem: Inglês

10.1096/fj.08-0601ufm

1530-6860

Gerald Weissmann,

Genetics, Aging, and Longevity in Model Organisms

POPE BENEDICT XVI SAYS AN IMMORTALITY PILL MIGHT NOT BE SUCH A GOOD THING. Vatican City: The 80-year-old pontiff says it's better not to hope for biological life that can be made to last forever (1). Drosophila melanogaster. DNA homologous recombination in red. Image courtesy of Mitch McVey, Tufts University, Medford, MA, USA. Eo and Tithonus Jug. Image courtesy Freud Museum, London, UK. The Drosophila mutant Methuselah (mth) was identified from a screen for single gene mutations that extended average lifespan. mth mutants have a 35% increase in average lifespan and increased resistance to several forms of stress. . .(2). I don't want to achieve immortality through my work; I want to achieve it through not dying. I don't want to live on in the hearts of my countrymen; I want to live on in my apartment (3). Woody Allen For reasons clear to His Holiness Benedict XVI, if not to Woody Allen, more folks bet on eternal paradise than on permanent rent control. Last March, while delivering a homily near St. Peter's Square, the pope reflected on the limits of science. Pleading for the faithful to “drink from the fountain of life itself,” i.e., spiritual immortality, he warned that extending life past its natural limits would crowd the world with old people. There would be no room on earth “for youth, for this newness of life” (4). I'm afraid, though, that his warning was a tad late; modern science has already helped break the biblical rule that “the days of our lives are threescore years and ten” (5). The pope has himself beaten the odds. Thanks to advances in medical management, the octogenarian pontiff has survived two strokes and congestive heart failure. Biological immortality might not lurk around the corner, but we're working on it. In the lab, thanks to the biological revolution, we've “immortalized” lines of human cells in a dish, cloned DNA from the dead, and extended by tenfold the natural lifespan of yeasts (6). Flies, worms, and rodents live up to 40% longer when fed a diet that has at least 30% fewer calories than usual (7), while resveratrol from red wine can keep them fit (8). Reporting on Leonard Guarente's analysis of how caloric restriction extends life, The New York Times enthused: “Actuaries, put down your gloomy mortality tables and sharpen your pencils. Heirs and legatees, contain yourselves in patience. If any such drug were to work in humans the same way that this diet of 30 percent less than normal calories works in laboratory rodents, people would start enjoying a maximum life span of 170 years, most of it in perfect health” (9). And sure enough, news came last summer that an immortality pill is nigh: “Super Fruit Fly May Lead To Healthier Humans; Aging Slowed With Single Protein” (10). Richard Roberts of University of Southern California (Los Angeles, CA, USA) and Seymour Benzer's group at California Institute of Technology (Pasadena, CA, USA) have made peptides that target the Methuselah (mth) gene in fruit flies. Insects with mutations in this gene have a 35% increase in average lifespan and increased resistance to several forms of stress, including heat, starvation, and oxidative damage. The protein affected by this mutation is related to a G protein-coupled receptor of the secretin family and is switched on by a ligand named Sun. By means of a novel mRNA display selection technique, which Roberts developed, the Pasadena group identified high-affinity peptides that bind to the N-terminal ectodomain of mth and prevent binding of Sun to its target (11). As humans, like flies, have secretin-like receptors on many of our cells, this sun-screen, as it were, could be a forerunner to the pontiff's “immortality pill.” As Woody Allen might say, we should live so long. And yet you ask me why I'm glum, And why my graver muse is dumb, Ah me! I've reasons manifold Condensed in one—I'm getting old When life, once past its fortieth year Wheels up its evening hemisphere. . . (12). These days, age 40 seems closer to noon than evening. American life expectancy is now nearly 80, and our maximum lifespan has also increased. The bean counters of Medicare predict that by 2010, they'll have 50,000 centenarians on their payroll (13). The trend is global: The oldest Swedes now die at age 108, eight years later than their counterparts in 1860 (14). The days of our lives are no longer threescore years and ten. A Chinese official boasts that “Chinese Life Expectancy Rises by 41 Years in One Century,” from just over 30 years in 1900 to 70.1 in 2000. He attributes the new longevity of China's people to “the advancement of science and technology, especially in medical science” (15). Pace, Pope Benedict, the Chinese young have not been crowded out by old folks. When the pontiff urged a moratorium on immortality pills, I'd bet that he was hooked up to a sound system manufactured by one of the 300 million Chinese under 25 who now walk the earth because of one or another pill. The longer the days of our lives, the longer the days of waning powers. There's that “Catskill” story about the 87-year-old man who marries an 83-year-old woman he met in a senior center. They take their honeymoon in a rented bungalow by the sea. The woman retires upstairs first and calls out to her husband, “Come upstairs and make love!” He replies, “I can't do both!” That is no country for old men. The young In one another's arms, birds in the trees —Those dying generations—at their song, The salmon-falls, the mackerel-crowded seas, Fish, flesh, or fowl, commend all summer long Whatever is begotten, born, and dies. Caught in that sensual music all neglect Monuments of unageing intellect. W. B. Yeats, “Sailing to Byzantium,” 1928 (17). …set upon a golden bough to sing To lords and ladies of Byzantium Of what is past, or passing, or to come (17). Yeats resigned from the Irish Senate for “reasons of health” in the year that the poem was published. Tattered and paltry, perhaps, but he stuck out the years of hobble and creak for 11 more years, until in W. H. Auden's words: “The current of his feeling failed; he became his admirers” (18). His admirers have kept Yeats very much alive: this spring, the film “No Country for Old Men” picked up four Oscars; Jonathan Spottiswoode's rock lyric “Sailing to Byzantium” is climbing the charts (19); and Philip Roth's “The Dying Animal” is in many of the bookstores (20). To what avail? Although Yeats may have achieved immortality through his work—and live on forever in the hearts of men—he's no longer living in his apartment. Unlike Yeats or the pontiff, Sigmund Freud was as skeptical of the afterlife as Woody Allen. At mid-life in the Vienna of 1911, Freud scoffed at spiritual immortality: “The doctrine of reward in a future life for the renunciation of earthly lusts is nothing but a mythical projection” (21). But age and illness convinced Freud that the land of pain is no country for old men. Aged 80 and exiled in London, mauled by bouts of surgery and radium treatment for oral cancer, Freud turned to the kindly Fates of the Greek myth: Seymour Benzer (1921–2007) with Wooden Model of Drosophila (ca. 1974) Image courtesy of the Archives, California Institute of Technology. Perhaps the gods are kind to us in making life more disagreeable as we grow older. In the end death seems less intolerable than the manifold burdens we carry (22). As he wrote these lines in his study, Freud was attended by a goddess. Eo, goddess of dawn, is limned in clay on an Athenian Lekythos, which stood by his desk. This red-figured oil jug, which dates to the 4th century BC, remains on view today in London's Freud Museum, and its name Lekythos remains in our vocabulary as lecithin, from the Greek for egg-yolk (23, 24). The graceful, spread-winged goddess is shown in pursuit of a beautiful youth with a lyre in his hand. The legend is that of Eo and Tithonus, a handsome mortal beloved by Eo. The goddess was so enamored of the young prince of Athens that she asked Zeus to make Tithonus immortal. He did, but she failed to ask Zeus to prevent Tithonus from aging. As time went on—as the fates wound down the string of life—he did indeed turn into a paltry thing: He aged, dried, and shrunk to the size of a cricket. And that's why crickets chirp at dawn. How can my nature longer mix with thine? Coldly thy rosy shadows bathe me, cold Are all thy lights, and cold my wrinkled feet Upon thy glimmering thresholds, when the steam Floats up from those dim fields about the homes Of happy men that have the power to die. . . (25). It's clear that what rickety-crickety Tithonus needed was a pill that would not only make him immortal but also keep him young enough to mix his nature (as it were) with Eo's. If only he had been around to hear the news from Cal Tech! Shrunken to insect stature, what would Tithonus not have given for a mutated mth gene, for that mRNA peptide library, for that pill from Pasadena? The woods decay, the woods decay and fall, The vapours weep their burthen to the ground, Man comes and tills the field and lies beneath, And after many a summer dies the swan (25). The action of the Huxley novel takes place a short “motor-car ride” north of Los Angeles. On this as-yet undeveloped site, a boorish tycoon has built a large mansion (half the San Simeon of Hearst, half the Huntington Library) that houses valuable, ancient manuscripts. An English scholar is sent to look into a sheaf of books and manuscripts that the mogul has acquired from an English earl; these date back over 300 years. The tycoon has hired a certain Dr. Obispo (sic) to inject him with an extract that will prolong his life. The extract is prepared from the intestinal flora of carp, whose life expectancy far exceeds that of humans. Obispo's biological experiments are based on the notions of Elie Metchnikoff, who won the Nobel Prize in 1908 for discovering phagocytosis. Metchnikoff suggested that we age because our intestinal bacteria generate toxic, oxygen-derived metabolites of fatty alcohols; these activate phagocytes of all stripes: macrophages and microphages (read neutrophils) and “neuronophages” (read glial cells). Dr. Obispo tests the effects of feeding carp intestines to mice: “The effect on the mice had been immediate and significant. Senescence had been halted, even reversed. They were younger at eighteen months than they had ever been” (26), just like Guarentes's starved mice or Benzer's fruit flies. The Athens of the twentieth century is on the point of emerging here in the Los Angeles Metropolitan area. I want Tarzana to be its Parthenon [for] Art, Philosophy, Science (27). No creative work, whether in engineering or in art, in literature or in science, has been the work of a man devoid of the imaginative faculty (28). Aldous Huxley would have been pleased that the California Institute of Technology is within a stone's throw of the Huntington Library, where from time to time is displayed a copy of The Ellesmere Chaucer, acquired by Henry Huntington in 1917 from the Third Earl of Ellesmere, whose family had owned it for 300 years. Huxley's Dr. Obispo might have been pleased were he to have learned that nowadays, we, too, link aging to oxygen-derived free radicals. Indeed, we have experimental evidence that not only secretin but also other gastrointestinal hormones such as VIP and gastrin share G-protein-linked receptors with ligands involved in phagocytosis, immunity, and that gene for longevity in the fly (2, 29, 30). Who would have thought it? Am not I A fly like thee? Or art not thou A man like me? For I dance And drink & sing: Till some blind hand Shall brush my wing. If thought is life And strength & breath: And the want Of thought is death; Then am I A happy fly, If I live, Or if I die (31). We have learned much about the life of flies and men, about Methuselah and Sun, and about other genes for “Time, Love, and Memory” (32) from the wise man who put the fruit fly on the map of Pasadena forever: Seymour Benzer (October 15, 1921-November 30, 2007). He, too, has become his admirers.