One of the eternal anthems by The Rolling Stones proclaims “Gimme Shelter”, but given the band members apparent immunity to aging combined with a new article from the lab of Maria A. Blasco (CNIO, Madrid, Spain), should the song now proclaim, “Gimme shelterin”?
The shelterin complex regulates telomerase activity and protects the telomeric regions at the end of mammalian chromosomes from recognition as DNA damage, and a previous study discovered that loss of a shelterin component (TRF1) caused loss of mouse tissue homeostasis. Based on these findings, the team now returns with a new study demonstrating that giving a mouse just a little more shelterin (by TRF1 gene therapy) promotes extended healthy aging!
So take it away maestro! What high notes does this new article hit?
- During normal aging of both humans and mice, TRF1 mRNA and protein levels decrease in most tissues
- This finding suggests that the age-related reduction in TRF1 levels occurring promotes telomere uncapping and telomere-induced DNA damage, leading to the detrimental signs of aging
- To boost TRF1 levels in mouse tissues, the group employed a non-integrative adeno-associated serotype 9 vector (AAV9-TRF1) to transiently overexpress TRF1
- Importantly, a previous study established that constitutive TRF1-overexpression leads to telomere cleavage by the XPF nuclease
- Given the non-integrative nature of the AAV9 vector, cell proliferation dilutes vector expression, thereby inhibiting the previously observed telomere cleavage
- AAV9 exhibits multiple other advantages, including low immunogenicity, high transduction efficiency in numerous tissues, and the ability to cross the blood–brain barrier
- Excitingly, transient TRF1-overexpression boosted neuromuscular coordination, glucose tolerance, and cognitive function in 2 year old mice and, in general, delayed physiological mouse aging
- However, TRF1 overexpression does not significantly affect median telomere length
- The authors did observe a lower abundance of short telomeres in muscle tissues and lower levels of telomere-associated DNA damage in hippocampal brain tissue (See Figure), suggesting that transient TRF1-overexpression inhibits the accumulation of short telomeres
- Additionally, TRF1-overexpression doesn’t increase cancer incidence or other unwanted side-effects over the natural lifespan of the mouse
So the take-home message of this terrific paper may be “Gimme shelterin” to promote healthy aging, but maybe turn the volume down?
However, if you really want to hear all the high notes and crashing drum solos from this paper, head over to Aging Cell, September 2017!