Sunday, January 10, 2010

Aging research: systems biology, genomics and new tools

Three important themes emerged from the Buck Institute’s Systems Biology Symposium of Aging held November 10-13, 2009. The themes were progress in the overall understanding of aging as a systems biology problem, the role of genomics in aging, and new tools development for aging research. Happily, some immediately applicable tidbits were discussed: the findings of the protective response of endurance exercise, and the use of resistance exercise as a countermeasure to sarcopenia. (Mark Tarnopolsky)

Theme 1: Aging is a systems biology problem
Increasingly, aging is being understood as a systems biology problem involving cascades of signals across multiple pathways, many of which break down with aging. In younger organisms, problems are managed automatically as they arise, but in older organisms, the resolution processes do not work as well. When cells become damaged as a consequence of aging, they can either self-destruct through apoptosis (regulated cell death) or become senescent (living on without dividing). Senescent cells persist in tissues, where they may secrete inflammatory proteins. Many major age-related diseases, including atherosclerosis, heart attack, stroke and metabolic syndrome, share an inflammatory pathogenesis. The build-up of senescent cells can lead to both degenerative disease (aging) and hyper-proliferative disease (cancer). There are some efforts underway to facilitate the removal of senescent cells, for example, using an MMP inhibitor to kill senescent cells.

Dynamic regulatory continua
It is being suggested that more and more aspects of living systems such as humans are dynamic regulatory continua, and that there may be optimum points on the continuum which become harder to maintain with aging. One example of a dynamic regulatory continuum is the interrelation of cholesterol, fats, and Alzheimer’s disease. Having lower levels of the 142 alpha-beta plaques is neuroprotective, for example, but higher levels become harmful. One technique for understanding dynamic regulatory continua is to look at explaining the events at one biological level in terms of the events at the levels above and below them. (John Tower)

Signaling pathways
There is more of an effort to examine whole processes such as pathway networks and the chain of events in DNA transcription and translation. Current knowledge of signaling pathways is fairly primitive. The role of mRNA translation is being investigated as it is known to be related to growth promoting activities like cancer. There is the general translation of RNA, but this can be further modulated by the cell. In addition, signaling pathways are not working alone, there are probably many pathways converging. For example, there is likely cross-talk between several important signaling pathways such as the insulin pathway, the TGF-beta pathway, the IGF-1 pathway, and the TOR pathway. (Heidi Tissenbaum) In another example of the systemic interactions of aging, amyloid-binding compounds were found to suppress protein aggregation models in concert with homeostatic function (i.e., autophagy, chaperones, etc.). (Gordon Lithgow)

Theme 2: The role of genomics in aging
As with many areas of biology and medicine, the role of genomics is becoming increasingly important in aging. While it is known that there is little variation (0.1%) among SNPs in human genomes, 12% of the genome may vary structurally (copy-number variations, deletions, inversions and insertions of genes). On the threshold of whole human genome sequencing, it is being realized that SNP data alone is insufficient for a genomic understanding of health; more levels of data and annotated data, potentially including RNA sequencing to see protein expression will be needed. (Mike Snyder)

Variation in genomes
Three areas of research were presented regarding genome variation and aging. First were the long-expected results of Boston University's genome-wide association study (GWAS) on centenarians. The study found 150 SNPs in the genetic signature of longevity, 33 of which meet genome wide significance and are replicated. The most important longevity genes, most already associated with aging pathways, were: IL7 (immune system), CDKN2B (tumor suppressor), and APOE, CTNNA3, TOMM40, SORCS1, and SORCS2 (Alzheimer’s disease). (Tom Perls)

Related results were confirmed by personal genomics company 23andme. A study of senior athletes found that this cohort exhibited lower risk than the database in general. Ten chronic disease conditions were reviewed including coronary artery disease, breast cancer, prostate cancer, heart attack, type 2 diabetes, high blood pressure, high cholesterol, and macular degeneration. (Joanna Mountain) However, other research found that there is not a full overlap between genes conferring longevity and genes conferring increased healthspan. (Monica Driscoll)

Variation in genomic expression
Four interesting research findings found variation in genomic expression between older and younger organisms. First, another centenarian study found significant diversity of microbial communities in different age groups. For example, there was a high level of expression of certain miRNAs in older livers (miRNA-200c, miRNA-141, and miRNA-31). (Claudio Franceschi) A second study found that a full third of genome expression changed with age in worms. (Simon Melov)

A third study found a general relaxation in translational control and protein production during aging. It was proposed that increased or sloppy protein expression might contribute to proteotoxicity. (Monica Driscoll) Applying a systems biology and network analysis approach, a fourth study looked at how the structure of biological networks declines with age. The AGEMAP (a gene expression database for aging in mice) was reviewed, finding 26% fewer edges (edge nodes on the network) in 24 month old mice vs. 16 month old mice. It is possible that gene expression networks could lose integrity with age. An unexplored but possible explanation is that if there if less transcription, then network edges disappear. (Daniel Promislow)

Theme 3: New tools development for aging research
New approaches and tools are critical to advancing the study and potential remedy of aging, and three interesting talks were presented. First, progress in microfluidics and microscopy was discussed, particularly an exceptional development in electron microscopy that may allow the noninvasive molecular-resolution imaging of live samples (Figure 1). Usually electron microscopy is a destructive technique as the electron beam destroys the sample in the process of inspecting it. (paper: Noninvasive Electron Microscopy with Interaction-free Quantum Measurements). (Fatih Yanik)

Figure 1: In vivo noninvasive molecular imaging.

Image credit:

A second area of improvement has been in the targeted analysis of specific proteins. Now that there are robust measures for mRNA, proteins and post-translational modifications are the next areas of interest. Traditional shotgun analysis techniques are being improved upon by targeted analyses of specific proteins using mass spectrometry. The process is to take a protein mixture, produce peptides through proteolysis, collect a snapshot of multiple peptides at once, and use mass spectrometry to separate them by their mass. This method greatly expands protein identification and analysis capabilities, including the ability to do time course experiments. (Mike MacCoss)

Third, a genomic database tool, PharmGKB, was presented. The database facilitates a systems approach to pharmacology. Researchers can search for pharmacogenes, for example, given a drug and putative indication, ranking all genes in the genome for the likelihood of interactions. The database contains information regarding over 500 drugs, 500 diseases, and 700 genes with genotyped variants as of November 2009. (Russ Altman)

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