DATE: January 16, 1997 REVISED: February 19, 1999

TO: Members

FROM: L. Stephen Coles, Co-Founder

SUBJECT: Homework Assignment No. 1 -- List of Top Ten Unsolved Problems in Aging Research

Prof. Joshua Lederberg, former President of Rockefeller University, once told me while he was Chairman of the Genetics Department at Stanford Medical School, "Pushing the envelope in science is more about knowing what questions to ask than it is about toiling in the lab. Once you have what you believe to be a good hypothesis, you've got to go back to the lab and get the needle to point slightly to the right or slightly to the left before you invest a lot more effort."

  Assignment No. 1: Generate and submit your own list of the "Top Ten Unsolved Problems in Aging Research." This assignment may be submitted by E-mail at any time (scoles@grg.org), but is formally due on February 10, 1997 at our next meeting. The criteria for this problem list includes well-defined Ph.D.-Thesis Topics that can be accomplished by a respectable graduate student in biology within a 1-2 year period. Another criterion is that a solution to the problem will advance our agenda (as defined in our Charter, posted on the web). The list will then be edited, compiled, and reviewed over the coming months to see if we can establish a consensus, after which we will post it in a conspicuous place on our LA-GRG home page for external comment.

 Other lists can be found in Strehler's "100 Unsolved Problems" [pp. 375-388, Bernard L. Strehler, Time, Cells, and Aging (2nd Edition; Academic Press, New York; 1977)] or in Finch's Agenda [pp. 4, 646-652, Caleb E. Finch, Longevity, Senescence, and the Genome (University of Chicago Press, Chicago, Illinois; 1990)]. My own list follows, but I suggest you generate your own list before looking at it, lest you be overly biased before you get started.

1. Centenarians: Demographics of Human Senescence... Johnny Carson regularly interviewed centenarians on the Tonight Show with the aim of amusing his audience with their curious, self-serving answers. When George Burns was asked at the age of 100 to what he owed his great longevity, he answered "Hard work and smoking at least one if not several cigars a day. By the way, when my doctors advised me to stop smoking, I always ignored them. Anyway it really doesn't matter; they're all dead!"

 The odds of reaching 100 years of age in most industrialized countries is now about 1 in 20,000 or 0.005 percent. In the U.S. there are on the order of 50-70K such individuals, many in nursing homes. Census numbers are soft on many of these alleged centenarians due to poor documentation. Birth certificates before the year 1900 were rarely recorded with precision, and social security numbers didn't exist at that time. For example, Shigechiyo Izumi of Japan was included in the Guinness Book of World Records as the longest-lived man at 120 years, but most experts now regard his death as "only" 105. The runner up was Pierre Joubert of Quebec, Canada at 113, but this too has now been debunked. The Shangri-La tales of superlongevous tribes in Vilcabamba, Peru and other places was discredited in the 1970s. The biblical patriarchs like Methuselah probably slipped a decimal point at 969 years.

 What is special about centenarians as a group, if anything, that explains their longevity? Can we learn anything from identical-twin studies of centenarian twins reared-apart that will distinguish genetic factors from environmental factors? Are there enough of such persons to even do a study? The French are conducting such a study on their own population. By the way, the world's oldest documented person was the French woman, Jeanne Calment, who passed away at 122 years of age. The oldest living male is now presumed to be Mr. Herbert Young of Harlem, New York at age 112. The second oldest living male is now 111 years. [Source: French demographer, Jean-Marie Robine] Can we set up a database to gather information as to their life styles, diet/fasting, alcohol intake, athletic ability, IQs, occupation(s), marriage(s), ages at death of all first-degree relatives and causes of death? Has the NIA ever proposed a study of Centenarian blood chemistry or anti-oxidant profiles?

2. Genomics: Understand the Genetics of Aging by Comparing the Genomes of Different Species: Yeast, Paramecia, Bristle Cone Pines (red herring), Nematodes ( C. Elegans), Fruit Flies ( Drosophila), Rock Fish, Tortoises, Mice, Rats, Bats, Elephants, Chimps, and Humans (searching for common so-called "gerontic" genes).

3. Caloric Restriction: What is the mechanism of life extension by dietary restriction? Is it related to body-temperature thermostats or basal metabolic rates? Is it related to a reduction in chaperon proteins (Prof. Spindler, UC Riverside) that leads to significant non-biologically active protein structural synthesis that triggers apoptosis and then subsequently increased cellular replication, which is the only thing that is really rejuvenating?

4. Telomere Shortening: What will telomerase do for longevity? Can the Hayflick Limit be made to exceed 50 +/- 10? [Revised Answer = Yes.] What about the Hayflick limit for paramecia, something over 200 mitotic divisions? However, post sexual conjugation, the telomeres are reset in some fashion. How?

Is telomere shortening directly proportional to the relentless linear decline with age in epithelial tissue repair efficiency in response to injury?

5. Progeria: What are the age-accelerating mechanisms of Downs, Progeria (Hutchinson-Gilford Syndrome), or Werner's Syndrome (helicase mutation)? Are these true metaphors for aging or are they merely cartoons of normal aging?

6. Mitochondria: What switches on the synthesis of new mitochondria and/or the scavenging of "burnt out" mitochondria (conversion to lipofuscin)? Do mitochondria go through a process of mitosis in response to signals from the nucleus about their average density in the cytoplasm? What dictates hypomitochondriosis? What rejuvenates mitochondria in eggs post fertilization (with a few exceptions, spermatic mitochondria never enter the egg after head penetration, so mtDNA is almost always feminine, the "original Eve")? Can fetal mitochondria be transplanted into old cells and function? Is the potential lifespan of all mitochondria and their progeny in dividing somatic cells no greater than 130 years, as extrapolated from semilog plots?

Click here to see what the pseudo-three-dimensional structure of mitrochondria looks like and a legend providing more detailed information about the images.

7. Human Growth Hormone: Can we develop oral secretagogues for all anterior pituitary hormones? Merck has given up a promising line of research for what appear to be marketing reasons.

8. Free Radicals: What do free radicals (tanning) and glycosylating agents (caramelization) have in common in promoting aging? And can they be reversed with antioxidants and/or solvents?

9. Nanotechnology: Could nanotechnology (c.f. Eric Drexler's books) be used to repair tissue damage, especially endothelial damage?

Click here to see a cartoon of how nanotechnology might be used to repair blood vessels.

Click on Zyvex, Inc. to find out how a Richardson, TX company plans to construct nanotechnology assemblers.

10. Compression of Morbidity Hypothesis: Will there be a "compression of morbidity" as we increasingly rectangularize the human longevity/mortality curves (as predicted by the James Fries of Stanford University)? In support of this notion, a recent study reported in the March 18, 1996 issue of PNAS suggests that Americans are now suffering fewer disabilities in their senior years. Other relevant papers have been reviewed in JAAM, Vol 1, No. 3.

If you have strong opinions about or are interested in working on one of these questions as a research topic, please link to Stanley R. Primmer's personal solution to Assignment No. 1 where you will find detailed discussions and provocative speculation at the "cutting edge" of gerontology research today. Any other solutions to Assignment No. 1 will be welcome. We challenge you to send your solution by E-mail to scoles@grg.org. A team of ten professionals from the LA-GRG will review and critique all entries, the best of which will be posted along with Stan Primmer's contribution on this site.