I spent last week at the Cold Spring Harbor meeting on the Molecular Genetics of Aging. Long Island is beautiful in the fall; this picture could have been taken while I was there:

Cold Spring Harbor

The meeting itself was at the same time exciting and grueling: There’s so much happening in the field right now; one has the feeling of drinking from a firehose…all day long…after staying up very late the night before, talking science on the deck of the Lab bar.

I’ve been struggling to find a way to summarize the event, and the contents of the meeting, but I’ve decided that a thorough conference review is beyond the scope of a blog entry. With a few days’ remove from the experience, however, I keep returning to one theme: This field has exploded in the last dozen years.

Without in any way meaning to denigrate the progress in study of aging prior the early 90′s, the specific field in question at this conference (molecular genetics of aging) barely existed then. Excellent work had been performed on the contribution of oxidative damage to the aging process, but while a broad consensus about oxidation’s significance had emerged, the specific details were often murky. Many believed that the eagerly anticipated identification of genes mutated in progeroid syndromes (e.g., Werner’s) would provide an entry point for work in humans and shorter-lived organisms, but at the time we were very short on genes and model systems.

Starting in 1993, however, that began to change. I want to single out two papers that mark the beginning of the era of a true molecular genetics of aging (for me, i.e., I don’t mean to discredit any other work done during the same period; I’m just able to see a pattern and tell a story about it, and that story involves these two papers, which I read as a graduate student). Both have had tremendous impact on the field over the ten years since — at the CSHL meeting, more than half of the talks were in some way based on the founding observations in these two papers.

First, Kenyon et al.‘s A C. elegans mutant that lives twice as long as wild type:

We have found that mutations in the gene daf-2 can cause fertile, active, adult Caenorhabditis elegans hermaphrodites to live more than twice as long as wild type. This lifespan extension, the largest yet reported in any organism, requires the activity of a second gene, daf-16. Both genes also regulate formation of the dauer larva, a developmentally arrested larval form that is induced by crowding and starvation and is very long-lived. Our findings raise the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation, daf-2 and daf-16 provide entry points into understanding how lifespan can be extended.

Since the publication of this paper, the DAF-2/aging story has been exhaustively studied in worm. Cloning of the genes involved revealed that DAF-2 encodes the worm Igf-1 receptor, a protein which is conserved throughout metazoa. Over the last decade, studies in flies and mouse reveal that Igf-1 signaling plays an essential role in the regulation of lifespan in many organisms. Igf-1 pathway connects the sensing of nutrient availability to the control of aging, and there’s currently a great deal of excellent work describing the role of this axis in the regulatory biology of calorie restriction. The Kenyon lab continues to elaborate on the story, with recent publications on DAF-2 and cancer; Kenyon lab alumnus Andrew Dillin made a big splash recently by connecting DAF-2 signaling with Alzheimer’s.

Second, Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae, by Kennedy et al. in the Guarente lab.

Aging in S. cerevisiae is exemplified by the fixed number of cell divisions that mother cells undergo (termed their life span). We have exploited a correlation between life span and stress resistance to identify mutations in four genes that extend life span. One of these, SIR4, encodes a component of the silencing apparatus at HM loci and telomeres. The sir4-42 mutation extends life span by more than 30% and is semidominant. Our findings suggest that sir4-42 extends life span by preventing recruitment of the SIR proteins to HM loci and telomeres, thereby increasing their concentration at other chromosomal regions. Maintaining silencing at these other regions may be critical in preventing aging. Consistent with this view, expression of only the carboxyl terminus of SIR4 interferes with silencing at HM loci and telomeres, which also extends life span. Possible links among silencing, telomere maintenance, and aging in other organisms are discussed.

I’m going to skip the long strange trip that this story took from the founding observation to its modern form, and jump to the end: This is the line of inquiry that eventually led us to SIR2 and its mammalian homologs, Sirt1-7. There is a small army (at least a division) of postdocs and graduate students around the world working on sirtuins, and the conference roster was stuffed with talks describing the tissue-specific functions of individual Sirt genes in the mouse. (For recent treatment of the subject in the published literature, see our articles on Sirt4 in the mitochondria of the pancreas, Sirt1 and senescence, and so on).

A decade or so is long enough to see a seminal observation turn into its own field, and in these cases I think we’ve seen it. It was a great pleasure to be witness to the most recent progress in these still-expanding bodies of work.

On a personal note, it was great to see Lenny and Cynthia sitting in the front row by the podium, soaking it all up, looking every bit the proud grandparents.

Well, almost every bit: they don’t look old enough to be grandparents.

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