Last year we heard about the counterintuitive observation that DNA repair mutants (which exhibit premature aging and shortened lifespans) have significant phenotypic and transcriptional overlap with genetically dwarfed or calorie restricted (CR) animals (which exhibit delayed aging and extended longevity).

The interpretation of those surprising results: Both DNA repair deficiency and CR cause organisms to divert resources away from reproduction and growth, and toward maintenance and repair. (It just happens to be fruitless for the DNA repair mutants, since they’re dumping energy into a compromised pathway.) Chalk one up for the disposable soma theory of aging.

Now, a follow-up paper from (basically) the same research group compares age-related transcriptional changes between mice aging normally, prematurely or slowly. The study, which includes data from multiple organ systems across the entire lifespan, confirms and expands on the observation that progeria and extended lifespan share common phenotypic features. From Schumacher et al.:

Delayed and Accelerated Aging Share Common Longevity Assurance Mechanisms Mutant dwarf and calorie-restricted mice benefit from healthy aging and unusually long lifespan. In contrast, mouse models for DNA repair-deficient progeroid syndromes age and die prematurely. To identify mechanisms that regulate mammalian longevity, we quantified the parallels between the genome-wide liver expression profiles of mice with those two extremes of lifespan. Contrary to expectation, we find significant, genome-wide expression associations between the progeroid and long-lived mice. Subsequent analysis of significantly over-represented biological processes revealed suppression of the endocrine and energy pathways with increased stress responses in both delayed and premature aging. To test the relevance of these processes in natural aging, we compared the transcriptomes of liver, lung, kidney, and spleen over the entire murine adult lifespan and subsequently confirmed these findings on an independent aging cohort. The majority of genes showed similar expression changes in all four organs, indicating a systemic transcriptional response with aging. This systemic response included the same biological processes that are triggered in progeroid and long-lived mice. However, on a genome-wide scale, transcriptomes of naturally aged mice showed a strong association to progeroid but not to long-lived mice. Thus, endocrine and metabolic changes are indicative of “survival” responses to genotoxic stress or starvation, whereas genome-wide associations in gene expression with natural aging are indicative of biological age, which may thus delineate pro- and anti-aging effects of treatments aimed at health-span extension.

Those last two sentences are very important, in that they address a critical issue in studies of transcription (indeed of any phenotype) as it changes with age. Given the observation that expression of gene X (or hormone Z) changes with age, one must next ask: How do we know whether this change reflects a causative feature of aging, a defensive response to another age-related change, a passive response of no great import, an epiphenomenon, or an artifact of the experimental system? (I’ve discussed this concern before, in the context of age-specific regulation of micro-RNAs.)

The authors would argue that the changes that are common to both progeroid and long-lived animals represent true protective/defensive responses to age-related stresses (according to the same logic that underlies the interpretation of the earlier work, discussed above). In contrast, those features shared between natural aging and progeria — of which there are far more — are signs of deterioration and decrepitude, and thus reflect age-related decline.

This logic is powerful: Having distinguished between these two classes of age-related transcriptional change, we’re far better equipped to start meaningfully measuring biological age.