An in-depth study charts the genetics involved in the shortening of life in response to mood and stress.
A team from Indiana University School of Medicine and the Scripps Research Institute, CA, conducted a multifaceted project investigating the genetic basis of premature aging in response to stress and psychiatric illness.
Using human participants and Caenorhabditis elegans, one of planet Earth's most-studied worms, the researchers delved into this intractable question.
They managed to identify a raft of genes that seem to control the impact of mood and stress responses on the longevity of an organism.
A gene called ANK3 (resource no longer available at www.nature.com) was of particular interest and appeared to play a key role in the process.
The role of ANK3
ANK3 codes for a protein called ankyrin-G. This protein is involved in certain types of synaptic transmission (messages being sent between neurons). Ankyrin-G has previously been associated with bipolar disorder, autism, and schizophrenia.
This gene is a prime candidate for uncovering the links between emotional responses and premature aging.
"We were looking for genes that might be at the interface between mood, stress, and longevity. We have found a series of genes involved in mood disorders and stress disorders which also seem to be involved in longevity."
Lead author Dr. Alexander B. Niculescu III
After analyzing the genes further, Dr. Niculescu and his team found that the genes in question changed their rates of expression with age. When examining the genes of individuals who experienced significant stress or mood disorders - for instance, people who had committed suicide - they noticed shifts in the expression of these genes.
The changes are of the type that would normally be associated with shorter lifespans and premature aging.
Earlier research, carried out by one of the co-authors of the current study, Michael Petrascheck, Ph.D., found that when C. elegans was exposed to mianserin - an antidepressant - the animals lived longer. This acted as the starting point for the current project.
Stress, aging, genes, and worms
To examine the roles of genes in mood, stress, and lifespan, the team embarked on a thorough program of experiments:
- Firstly, the team investigated the genetic changes mianserin made to C. elegans. The drug was found to affect 231 genes that were then cross-referenced to the human genome. In total, 347 corresponding, similar genes were identified in humans.
- These 347 genes were compared with the genomes of 3,577 older adults. Of these genes, 134 overlapped with depressive symptoms in humans.
- The researchers used a database containing genes already known to be involved in psychiatric disorders. They also used Niculescu lab's Convergent Functional Genomics approach to prioritize the genes in order of their involvement in mood and stress disorders. The top scoring gene was ANK3, a gene that is becoming well known for its role in psychiatric disorders.
- Focus then shifted back to C. elegans. The team used strains of the worm that had been bred with inactive ANK3 genes. These worms were tested under the effects of mianserin and oxidative stress. ANK3 is known to increase with age and mianserin keeps these levels down. However, they found that mianserin needs at least some ANK3 to provide its life-extending effects.
- Next, 700 blood samples from psychiatric patients and people who had committed suicide were examined. ANK3 was found in higher levels in older patients and those who had committed suicide.
- A panel of biomarkers was collected by adding some of the other high-scoring genes from the Convergent Functional Genomics investigation. When taken as a group, they gave an even stronger result than ANK3 on its own. The correlation was particularly strong for the suicide group, showing that the cluster of genes the team had identified did seem to play a role in psychiatric conditions.
The next question is how these genes might affect longevity. It was shown that the genes that overlapped most with mood- and stress-modulated longevity seemed to be involved in mitochondrial dysfunction. This relationship makes sense; a link between mitochondrial dysfunction and aging is steadily growing support from other research.
The authors of the study conclude that "these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress, and lifespan, that may be biomarkers for biological age as well as targets for personalized preventive or therapeutic interventions."
As ever, more work will be necessary to back up the findings, but the thorough nature of the investigation and its agreement with other studies gives future researchers a strong platform to build upon.