A 118-year-old Frenchwoman named Jeanne Calment is theoldest known person in the world. She lives in the South-of-France city of Arles and still remembers seeing the artistVincent van Gogh (1853-1890), who painted the flowers andscenes of Arles in 1888.
Calment is officially certified in France as the oldest livinghuman being, said biologist Franois Schchter, who heads theLaboratory of the Genetics of Aging in Paris. She is one of 338people 100 years of age or older enrolled in a research projectto investigate the relationship between longevity and geneticinfluences.
Schchter's lab is part of the Human Polymorphism ResearchCenter, whose director, Daniel Cohen, is a co-founder ofMillennium Inc. of Cambridge, Mass. (see BioWorld, Aug. 4,1993).
The first longevity influence that the Genetics of Aging lab isstudying compares two genes linked to cardiovascular disease(CVD) -- which is among the leading causes of death -- in thegenomes of their centenarians with 160 French adult controls20 to 70 years of age.
Unexpectedly, Schchter and his co-workers found that ACE/D,"a variant of ACE (angiotensin-converting enzyme) thatpredisposes to coronary heart disease, is surprisingly morefrequent in centenarians." The researchersU paper reporting thisparadox appears in the current issue of Nature Genetics as"Genetic associations with human longevity at the APOE andACE loci."
APO stands for "apolipoprotein," the protein component of HDL,LDL and VLDL PP the familiar cholesterol-carrying high-, low-and very low-density lipoproteins. The longevity lab examinedthe genetic variants in the genes encoding ApoE and ACE.
ApoE's three variants, or alleles (e2, e3 and e4), they reported,"have a major impact on total and LDL-cholesterol levels in theserum, which in turn are highly correlated with risk foratherosclerotic cardio-vascular disease." Not surprisingly, theydiscovered that ApoE's hyperchol-esterolemia e4 allele, "whichpromotes premature atherosclerosis, is significantly lessfrequent in centenarians than in controls." On the other hand,e2, which is associated with hyperlipidemia (excess fat in theblood), "is significantly increased" in the 100-and-over agegroup.
How do the researchers account for the curious frequency ofthe ACE gene's high-risk D allele in the centenarians' genome?ACE is an enzyme that acts as a governor in regulating thebody's blood pressure. Many patients with high blood pressureowe their hypertension to overactive ACE and receive an ACEinhibitor as therapy.
High blood pressure correlates with heart attacks, so what isthe "bad" ACE gene's D variant doing in centenarian DNA? Forone thing, Schchter noted, although ACE/D increases theenzyme's concentration in plasma, "it is unrelated to bloodpressure and hypertension in adult populations." Thisincongruity, in turn, suggests another: "higher blood pressure(appears) to be a positive survival factor in centenarians."
Yet another explication is that besides its role in blood-pressure control, ACE acts on neuroendocrine functions,suggesting "that an adaptive response to increasing needs mayoccur during aging."
A Swedish study of 85-year-olds showed that 13 percent hadlate-onset Alzheimer disease, associated with ApoE's e4isozyme. With a 42.2 percent three-year mortality rate,Schchter noted, "this population will have virtuallydisappeared before reaching 100 years of age." That wouldhelp explain the decrease in e4 carrier frequency between non-agenerians and centenarians.
"We are now looking for other candidate genes andsystematically screening the genome," he told BioWorld. In thisongoing work, his group is typing paired siblings for sharedalleles, "as we have no families among our centenarians."
Another new project is looking at some central feature of theaging process that takes place in each and every cell of theorganism. "Then we may fit genes that are really central to theaging process, that control the aging rate," said Schchter. He istrying to do this in vitro with long-term cultures oflymphocytes from the centenarians.
Overall, the group's research so far "provides mixed clues" tothe multiple gene effects in the DNA of Calment and hercohorts, Schchter observed. He summed up the lesson oflongevity research in one word: complexity. "So far, it hasbrought us problems, not answers," he said. He has reached noconclusion as to the ACE mismatch.
One of the founding grandfathers of basic aging research isLeonard Hayflick, who developed the Hayflick number, whichdescribes the cellular basis of senescence. Hayflick, who teachesanatomy at the University of California, San Francisco, School ofMedicine, is familiar with the current French centenarianproject.
"Schachter's contribution is clearly unique," Hayflick toldBioWorld. "It's the first extensive examination of specific geneloci in a very old human population, and I'd say it's amilestone." He added that "it is very important, if for no otherreason than to hopefully attract attention to this field bygeneticists and molecular biologists, who have historicallyneglected research in the field of fundamental biology ofhuman longevity and aging."
Hayflick is a scientific consultant to Geron Corp. of MountainView, Calif., which is pursuing pharmaceutical approaches tocontrolling the aging process (see BioWorld, June 4, 1993).
The French lab's centenarian population now totals more than400, with 40 percent dying each year. Schchter and his co-workers are keeping their fingers crossed that their 118-year-old Arlesienne will make it to age 120.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.