Talks in this session:
- McGee: Loss of intestinal nuclei with age in C.elegans
- Mookerjee: UCP proteostasis and implications toward lifespan
- Furman: Human immune system aging, vaccination and longevity
Matt McGee (Buck Institute; Melov lab) — Loss of intestinal nuclei with age in C.elegans
Despite the importance of C. elegans in the biology of aging, there is currently no comprehensive source of information about the changes in anatomical structure that occur over the worm lifespan. Or at least, until recently, there wasn’t.
McGee set out to assemble a 3D digital atlas of aging, comparing the anatomy of tissues in 4-day-old (“young”) and 20-day-old (“old”) worms. Essentially he has taken thin latitudinal sections along the entire length of young and old worms, stained them, aligned them, and used the slices to reconstruct a full 3D model of all tissues.
The images themselves are stunningly detailed – each worm is a whole universe. The age-related tissue degeneration McGee observes is striking; the slices barely look like members of the same species. Young worms are very similar to one another, but old worms exhibit highly varied morphologies.
One of the most significant changes occurs in the intestinal lumen, which degrades and collapses with age. The lumen diameter becomes irregular; microvilli diminish and disappear. Cell nuclei, as visualized with DAPI, are also lost in old worms – from a tight average of 30 on day 4 to a wide range at day 20; in the interim, the nuclei shrink before they start to disappear. This nuclear loss appears not to be due to apoptosis or germ line swelling (it still happens in ced-3 and glp-4 mutants).
The 3D Worm Atlas of Aging is coming along very nicely: Multiple old and young worms have been sectioned and imaged, with 3D segmentation of tissues. McGee and his collaborators have also imaged multiple individuals with confocal microscopy, respectively allowing greater detail and the use of fluorescent markers.
- From microscopy, we move on to mitochondria…
Shona Mookerjee (Buck Institute; Brand lab) — UCP proteostasis and implications toward lifespan
This work focuses on the mitochondrial UCP (uncoupling) proteins. Mitochondrial uncoupling modulates both the protonmotive force and ROS production; small changes in PMF can result in large changes in ROS production. (Conversely, a small amount of uncoupling can make a big difference in the amount of ROS production).
There are multiple UCP proteins: UCP1 is the canonical thermogenic protein found in brown fat, whereas UCP2 and UCP3 are expressed in other tissues – UCP2 in organs (pancreas, lung, CNS, spleen) and UCP3 in muscle, i.e., in “supply”-type cells and “demand”-type cells. These proteins are important in different contexts, as a function of glucose availability and other factors.
The non-canonical UCPs are known to modulate the “healthspan”: UCP2 plays a role in both diabetes and cancer. In the latter disease, UCP2 is upregulated in tumors, and has been associated with resistance to chemotherapy. During “normal” aging, UCP2 levels increase, resulting in a rise in proton leakage across the mitochondrial membrane.
UCP2 and UCP3 are rapidly degraded in a proteasome-dependent manner, which poses a challenge: the proteasome is in the cytosol, whereas the UCPs are in the mitochondrial inner membrane. Mookerjee proposes a model in which a ubiquitin tag is attached to the UCP, and subsequently “stitched” back across the outer membrane to the cytosol. To test the hypotheses, she has reconstituted UCP degradation in vitro, allowing determination of the biochemical requirements.
What is the purpose of rapid UCP2/3 turnover? Possibilities include regulation of activity or the management of a threshold response. It is clear, Mookerjee argues, that the proteostatic regulation of UCP2/3 are important for sustained mitochondrial function throughout the lifespan.
- What does a healthy immune system look like?
David Furman (Stanford; Davis lab) — Human immune system aging, vaccination and longevity
Not all people respond equally to to the same pathogens, and one of the principal sources of inter-personal variation is chronological age. Older people are exponentially more likely to die of SARS than young people; likewise, the seroprotection rate of vaccination drops significantly in old age.
It’s difficult to quantify the efficacy/competence of a given person’s immune system. How can we address this challenge?
Furman looked at the response of 85 individual human subjects to vaccination, making a wide range of measurements (antibody titer, cytokine levels, gene expression), with the goal of creating a classifier system that can be used to predict the efficacy of the immune response.
Young people tend to respond to antigen very similarly to one another (i.e., efficiently), whereas elderly subjects were split into two categories: cytokine responders and non-responders. These categories correlated with expression of genes associated with longevity, suggesting that immunosenescence and longevity represent two sides of the same coin.