Today I'll point out one representative example of the many ongoing research programs investigating the details of gene expression changes that occur with aging. Gene expression is the name given to the collection of processes that, step by step, act to manufacture proteins from their DNA blueprints, the genes. The pace of protein production changes in accordance with epigenetic modifications to DNA, and varying levels of proteins lead to alterations in cellular operation, which in turn feed back into further epigenetic modification processes. A living cell is a collection of countless feedback loops between its machinery, the pace of protein production, epigenetic decorations on DNA, and the surrounding environment. This cellular metabolism is enormously complex, and the ways in which it reacts to the changing environment and growing levels of cell and tissue damage over a lifetime are similarly complex. That damage, the root cause of degenerative aging, is the same for every individual, however, and so there are characteristic patterns to be found in epigenetic changes in aging.
Some research groups are presently gathering data on these patterns to try to build robust biomarkers of biological age, useful measures that might help speed up progress in longevity science by allowing fast validation or rejection of potential strategies, as well as an on-the-spot assessment of their estimated effect on life span. That remains a work in progress. Beyond this unified approach, I think we will also see a lot more in the way of ad-hoc measures of epigenetic changes adopted by single research groups or even for single studies. The paper quoted below is an example of the type; the researchers use measures of gene expression to support their particular interpretation of what a life-extending intervention is actually doing under the hood in the nematode worms used in the study. Beyond this, I should say, this is just another modest slowing of aging in a short-lived species, something that can now be achieved in scores of ways, and is of little relevance to human rejuvenation research. Drug interventions with large effects on longevity in short-lived species have very small or no effects in longer-lived species, and adjusting the operation of metabolism through drugs and the like is a dead end for meaningful human life extension. Next to nothing will come of it; the only viable path ahead towards radical healthy life extension of decades and more in the foreseeable future is that of damage repair, such as the SENS research programs.
That said, it doesn't make this research uninteresting; a great deal of the work that takes place in the aging research community, and which will do little for human longevity, is nonetheless both fascinating and enlightening. This research is an example of the way in which epigenetics is becoming a useful, necessary part of a wide range of research into aging, improving the output of the scientific community.
Tests showed that a drug capable of prolonging life in nematodes by more than 30% worked by expanding only young adulthood, and had no effects on later life stages. The scientists made their discovery while testing a long list of compounds for any that might prolong the short lives of the short worms. When early hints suggested that the antidepressant mianserin extended their lifespan, the scientists set about testing it more thoroughly.
The group found that as normal, water-fed worms aged, their gene activity changed from being precisely coordinated to ever more disorganised. Genes that were involved in the same bodily function, and which usually worked together, began working against one another. The researchers call this loss of genetic orchestration "transcriptional drift" and after examining data from mice and from 32 brains of humans aged 26 to 106 found that the same process occurs in both. The scientists went on to develop a test that used genetic disorder as a measure of the age-related changes that happen from youth until old age. When they ran the test on worms fed on mianserin, they found that the drug suppressed transcriptional drift, but only when it was given early enough. "Based on their gene expression pattern, 10 day old worms looked seven days younger. What happens is the period of young adulthood is made longer, whilst all the rest that comes later stays the same. The life extension comes only from increasing the young period of life, and then when this period is over, the compound doesn't do anything any more."
We classified gene expression changes for groups of genes into two types. Type I changes describe whether the overall expression across an entire functional group/pathway increases or decreases i.e. whether the pathway is up or down regulated with age. Type II changes describe the relative changes in gene expression among genes within functional groups with respect to each other. We named the type II change transcriptional drift. As animals age, genes within functional groups change expression levels in opposing directions resulting in the disruption of the co-expression patterns seen in young adults.
In this study, we have analyzed the dynamics of aging C. elegans transcriptomes and how these dynamics are affected by mianserin treatment. In C. elegans, transcriptional drift continuously increases with age across the transcriptome, substantially altering stoichiometric balances observed in young animals. Longevity mechanisms induced by either pharmacologically blocking serotonergic signaling or by blocking insulin signaling by daf-2 RNAi attenuate transcriptional drift. Abolishing lifespan extension by these mechanisms by either blocking serotonergic signaling too late (mianserin, day 5) or by addition of daf-16 RNAi (daf-2) abolished the attenuation of transcriptional drift.
Using transcriptome-wide transcriptional drift values as a metric for age showed that mianserin treatment attenuated the age-associated increase of transcriptional drift, thereby preserving the characteristics of a much younger (~3 days-old) transcriptome up to chronological day 10. These results showed that mianserin caused a 7-8 days delay in age-associated transcriptional change and suggested that the physiological changes leading to a lifespan extension were already completed by day 10. Measuring mortality levels supported this conclusion. By day 12, the entire mortality curve was shifted parallel by 7-8 days showing that the physiological delay leading to a lifespan extension was already completed. Experiments in which animals were exposed to mianserin for limited periods of time confirmed that mianserin exposure for the first 5-10 days of adulthood was necessary and sufficient to fully extend lifespan. The most parsimonious explanation that accounts for all these results is that mianserin treatment slows degenerative processes specifically between day 1 and 10, extending the duration of the period of young adulthood thereby postponing the onset of major mortality around mid-life.