Accumulation of short/damaged telomeres with increasing age is considered one of the main sources of aging-associated DNA damage capable of causing loss of the regenerative capacity of tissues and systemic organismal aging both in humans and mice with impaired telomerase activity.
Telomeres are caps of repeating DNA at the ends of our chromosomes that protect our genes from damage. Telomeres are often referred to as our clock. Every time our DNA replicates and our cells divide, our telomeres get a little shorter, and our clock ticks a little closer to our death at midnight. The shorter our telomeres, the more damage our DNA incurs — damage which is highly correlated with aging.
But luckily, there’s an enzyme, telomerase reverse transcriptase (TERT) which can polymerize new telomeric repeats and add these to the ends of our DNA, helping us live longer. As expected, overexpression of this enzyme in cancer-resistant mouse systems has been shown to increase longevity. Ever since the discovery of this enzyme, many scientists have hoped that we can use gene therapies involving this enzyme to extend the human lifespan. Now I’m happy to announce that, very recently, researchers in Spain have gotten us one step closer to this goal.
Two perspectives of the catalytic subunit of TERT from Tribolium castaneum: (left) electrostatic surface map and (right) ribbon diagram.
These researchers explored a TERT gene therapy in mice using a new adeno associated viral (AAV) vector which is able to cross the blood-brain barrier. One month after injection of the TERT-AAV in 1 & 2 year old mice groups, the researchers found significant increases in expression of TERT in the liver, kidney, lung, heart, brain, and muscle compared to the control.
After noting increases in the amount of active TERT expressed in these tissues, they next studied a variety of biomarkers related to aging to see if TERT was providing any aging-related benefits. As mice (and humans) age, they tend to lose bone mineral density and subcutaneous adipose tissue, become glucose intolerant and insulin resistant (marked by increased insulin levels), and their cognitive abilities, coordination, and balance degrade. Compared to the control group, mice treated with the TERT-AAV had higher bone mineral density, thicker subcutaneous layers, lower insulin levels, improved coordination and balance, and improved neuromuscular coordination — all signs of slowed aging progression! Interestingly, the more aged 2-year old mice tended to show greater improvement in these areas than younger 1 year-old mice subjected to the gene therapy.
Not only were there improvements in the biomarkers relevant to aging, but TERT-AAV treated mice also showed increased longevity compared to the control group (as illustrated below).
Graph showing percent survival of three groups of mice over time. Color-coding is as follows: mice treated with TERT-AAV gene therapy (black), mice treated with AAV vector containing protein unrelated to aging outcome (grey), mice treated with no gene therapy at all (blue).
Unfortunately, TERT overexpression is a common feature of cancer, due to TERT’s ability to confer “unlimited proliferative potential”, so the most foreseeable problem with a TERT gene therapy would be increased incidence of cancer. Remarkably, however, this study did not find a higher incidence of cancer in mice treated with the TERT gene therapy!
I hope other laboratories will quickly follow up on this exciting preliminary study, so we can hopefully get this gene therapy to human clinical trials soon. Who would have thought 114 years ago, when the first virus was discovered, that today we would be engineering our own viruses to infect us with beneficial genes to extend our lifespans. If this gene therapy is as effective in humans as it is in mice, the average life expectancy may increase from 78 to 94! Wouldn’t that be amazing?