Sunday, December 05, 2010

Bay area aging meeting summary

In the second Bay Area Aging Meeting, held at Stanford on December 4, 2010, research was presented regarding attempts to further elucidate and characterize the processes of aging, primarily in model organisms such as yeast, C. elegans (worms), and mice. A detailed summary of the sessions is available here. The work spanned some repeating themes in aging research:

Theme: processes work in younger organisms but not in older organisms
A common theme in aging is that processes function well in the first half of an organism’s life, then break-down in the second half, particularly the last 20% of the lifespan. In one example, visualizations and animations were created from the 3D tissue-sectioning of the intestine of young (4 days old) and old (20 days old) C. elegans. In the younger worms, nuclei and cells were homogenous and regularly spaced over the course of the intestine running down the length of the worm. In older worms, nuclei disappeared (an initial 30 sometimes ultimately dropped to 10), and the intestine became twisted and alternately shrunken and convoluted due to DNA accumulation and bacterial build-up.

Theme: metabolism and oxidation critically influence aging processes
Two interesting talks concerned UCP2 (mitochondrial uncoupling protein 2), an enzyme which reduces the rate of ATP synthesis and regulates bioenergy balance. UCP2 and UCP3 have an important but not yet fully understood role in regulating ROS (reactive oxygen species) and overall metabolic function, possibly by allowing protons to enter the mitochondria without oxidative phosphorylation. The mechanism was explored in results that worm lifespan was extended by inserting zebrafish UCP2 genes (not natively present in the worm).

Theme: immune system becomes compromised in older organisms
Two talks addressed the issue of immune system compromise. One team created a predictive analysis that could be used to assess an individual’s immune profile and potential response to vaccines by evaluating demographics, chronic infection status, gene expression data, cytokine levels, and cell subset function. Other work looked into the specific mechanisms that may degrade immune systems in older organisms. SIRT1 (an enzyme related to cell regulation) levels decline with age. This leads to the instable acetylation of transcription factor FoxP3 (a gene involved in immune system response), which suppresses the immune system by reducing regulatory T cell (Treg) differentiation to respond to pathogens.

Theme: systems-level understanding of aging processes
Many aging processes are systemic in nature with complex branching pathways and unclear causality. Research was presented regarding two areas: p53 pathway initiation and amyloid beta plaque generation. P53 is a critical tumor suppressor protein controlling many processes related to aging and cell maintenance: cell division, apoptosis, and senescence, and is estimated to be mutated in 50% of cancers. Research suggested that more clues for understanding the multifactorial p53 pathway could come from SnoN, which may be an alternative mechanism for activating p53 as part of cellular stress response. Neurodegenerative pathologies such as Alzheimer’s disease remain unsolved problems in aging. For example, it is not known if the amyloid beta plaques that arise are causal, or a protection mechanism in response to other causal agents. Some research looked at where amyloid beta is produced in cells, finding that after the amyloid precursor protein (APP) leaves the endosome, both the Golgi and a related recycling complex may be related in the generation of amyloid beta.

Theme: lack of conservation progressing up the model organism chain
Aging and other biological processes become more complicated with progression up the chain of model organisms. What works in yeast and worms may not work in mice, and what works in mice and rats may not work in humans. Some interesting research looked at ribosomal proteins, whose deletion is known to extend lifespan in model organisms. The key points were first that there was fairly little (perhaps less than 20%) overlap in lifespan-extending ribosomal protein deletions conserved between yeast and worms. Second, an examination of some of the shared deletions in mice (especially RPL19, 22, and 29) found some conservation (e.g.; RPL29), and also underlined the systemic-nature of biology, finding that other homologous genes (e.g.; RPL22L (“-like”)) may compensate for the deletion, and thereby not extend lifespan.

Theme: trade-offs is a key dynamic of aging processes

The idea of trade-offs is another common theme in aging; the trade-offs between processes, resource consumption, and selection. Exemplar of this was research showing that the deletion of a single gene involved in lipid synthesis, DGAT1, is beneficial and promotes longevity in mice when calories are abundant, but is also crucial for survival in calorie restricted situations. This supports the use of directed methylation to turn genes on and off in different situations. More details were presented in a second area of trade-offs: reproduction-lifespan. It is known that reproduction is costly and organisms without reproductive mechanisms may have extended lifespans. Research examined the specific pathways, finding that Wnt and steroid hormone signaling in germline and somatic reproductive tissues influenced worm longevity, particularly through non-canonical (e.g.; not the usual) pathways by involving signaling components MOM-2/Wnt and WRM-1/beta-catenin.

Academic aging research is continually making progress in the painstaking characterization of specific biological phenomena in model organisms, however the question naturally arises as to when and how the findings may be applied in humans for improving lifespan and healthspan. In fact there is a fair degree of activity in applied human aging research. Just as more individuals are starting to include genomic medicine, preventive medicine, and baseline wellness marker measurement in health self-management, so too are they consulting with longevity doctors. One challenge is that at present it is incumbent on individuals to independently research doctors and treatments. Hopefully in the future there could be a standard list of the anti-aging therapies that longevity doctors would typically offer. Meanwhile, one significant way for an individual to start taking action is by self-tracking: measuring a variety of biomarkers, for example annual blood tests, and exercise, weight, nutritional intake, supplements, and sleep on a more frequent basis.

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