Attentive readers will notice that I’ve skipped a couple of sessions: Session III was “oral presentations from abstracts,” a series of unrelated short talks; Session IV was a poster session, and Session V was a series of talks about mitochondria that I watched from the bar, where taking out my laptop might have risked a catastrophic beer spill, so I didn’t blog it.

This morning is a session on subjects near and dear to my own heart.

John Sedivy kicked off the series with a discussion of assays for detecting cellular senescence in vivo and in vitro. This is an incredibly important subject, since the current assays have a lot of problems, ranging from poor quantifiability to frank irreproducibility. The Sedivy lab has developed a large number of image-processing protocols that will allow reliable detection and quantitation in multiple system. These techniques will hopefully allow us to nail down once and for all the location, origins, fate, and function of senescent cells in aging tissues. (Heidi Scrable said during questions that her lab has developed a way to do immunohistochemistry after SA ß-gal, a twitchy technique that usually ruins a sample for subsequent analysis; I will definitely be going to that poster this afternoon.)

Next up was Darren Baker, who is doing genetics with progeroid mice: In the BubR1 progeria model, loss of p19 or p53 results in accelerated aging, implying that p53 is involved in delaying aging in vivo. This directly contradicts the idea that p53-induced senescence is a cause of aging, and enters the fray on the side of scholars who believe that properly regulated p53 has a primarily anti-aging function.

Alex Bazarov asked whether p16-induced senescence is reversible in breast cancer cells (it isn’t), and proposed using a small molecule inducer of p16 arrest as a cancer therapy.

Oliver Bischof demonstrated that repetitive DNA is transcribed at the onset of senescence, generating a population of small noncoding RNAs that are sufficient to induce both senescence-associated heterochromatic foci (SAHFs) as well as the senescence growth arrest itself. Note that these small RNAs are distinct from micro-RNAs, whose role in senescence and cancer was the subject of several posters at this meeting (including one by me).

Kan Cao studies progerin, the derivative of Lamin A that is responsible for Hutchinson-Gilford Progeria Syndrome (HGPS). Today’s talk focuses on the role of progerin in normal aging: Normal cells express progressively more progerin as a function of age, but telomerase-immortalized cells express hardly any. Thus, there may be a synergy between telomere shortening and progerin induction during cellular senescence.

Norm Sharpless shared human genetic evidence that variations in the p16/INK4a locus are associated with variations in the rate of aging, cancer, and other age-related diseases (specifically atherosclerosis). The overall results suggest that p16 has diverse effects in different tissues.

Vera Gorbunova discussed the distinct tumor suppressor mechanisms that have evolved in rodents of varying body size and lifespans. She began by introducing the negative correlation between telomerase activity and body size, and between in vitro replicative lifespan and body size. Larger body size means more cell divisions and a greater cancer risk; hence replicative senescence is more common among larger rodents. Another sort of control is observed in naked mole rats, which are long-lived and whose cells exhibit multiple forms of contact-mediated growth arrest. I especially enjoyed the talk because of my recently stoked interest in comparative biogerontology.

On to other exotic organisms: Fish! Our finned friends are getting into the biogerontological act — it was only a matter of time. Shuji Kishi talked about genetic screens in zebrafish that identified mutants showing alterations in senescence-associated biomarkers (specifically, the senescence-associated beta-galactosidase, aka SA ß-gal). One of the mutants he described is deficient in telomere maintenance, and exhibits segmental progeria as well as shortened lifespan; another mutant causes accumulation of lipofuscins, suggesting a defect in lysosomal metabolism or autophagy.

Valery Krizhanovsky, who works right here at Cold Spring Harbor in Scott Lowe’s lab, described a useful function for cellular senescence beyond its well-documented tumor-suppressor function: prevention of liver fibrosis. Senescent cells are present in fibrotic liver in wildtype animals, but in cell-specific p53 knockouts these senescent cells are missing. The senescent hepatic cells appear to attract immune infiltration, which work to clear the senescent cells and in the process alleviate the fibrosis.

Francis Rodier (from the Campisi lab, where I also work) presented his work on the relationship between persistent DNA damage, senescence growth arrest, and the senescence-associated secretory phenotype (SASP). He focused on the regulation of the SASP by an upstream kinase in the DNA damage response pathway — a seminal example of the connection between the chromatin lesions in a compromised genome and the regulation of cell-cell communication.


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