Healthy human life expansion has long been relegated to the realm of science fiction. New research harnessing an endemic virus for gene therapy has successfully extended mice lifespans, providing new hope for human longevity research.
In an exciting development for healthy ageing and gene therapies, published in PNAS, a multicentre team of researchers has effectively extended the lifespan of mice by 41%. They extended the length of telomeres and improved physical and neurological function without incurring an increased cancer risk.
Gene therapy delivery
In the present study, researchers determined the impact of a high-capacity cytomegalovirus vector (CMV) on factors like follistatin (FST) and telomerase reverse transcriptase (TERT) that protect against the influence of aging on human health.
CMVs can carry large genetic loads and do not integrate their own DNA into the host genome. This makes for an ideal vector for gene therapy delivery and CMV is already widely used in immunotherapies.
FST is a negative regulator of myostatin in muscle cells and has an important role in skeletal muscle development.
Telomere attrition, in which telomeres get shorter with each division, limits the number of times somatic cells can divide and contributes to ageing and organ decline. TERT reduce the erosion of chromosomal ends in mitotic cells. Previous research has demonstrated that gene therapies restoring TERT can extend lifespan in mice.
Effective administration with temporary results
Mouse CMV (MCMV) vectors expressing either FLAG-tagged TERT or FST genes (MCMVTERT and MCMVFST) were constructed.
Treatments were delivered intra-nasally or by injection. Both forms of delivery were found to be effective, though the effects were not permanent. TERT proteins in the blood of 8-month-old mice tested over a one-month period following administration showed a peak at 7 days, gradually declining to baseline by day 25. Monthly administration is required for continuous effects.
In humans, this could be advantageous when treatment indications do not require permanent expression of the therapy, but rather targeted and at specific times. This could reduce the risk of long-term consequences where any adverse reactions occur.
Mice were administered either the TERT or FST treatments from the age of 18 months onward, the human equivalent of around 56 years old. One mouse per group was sacrificed at 24 months old for tissue analysis, while the remaining subjects were monitored for physical and physiological changes until their natural death.
Healthier and longer lifespans
Mice given MCMVFST treatment lived for nearly 3 years; 9 months longer than the control groups. Mice receiving MCMVTERT lived for about 2 months longer than the MCMVFST group. One mouse achieved the equivalent of supercentenarian status in human terms, living to 41.2 months of age. Control group mice had all died of age-related causes before a single vector-treated mouse died.
Telomeres were directly examined and the average telomere length in the MCMVTERT group was tripled from the baseline. Levels almost reached those seen in much younger animals in all organs studied, including the brain, muscle, heart, lungs and liver. There was no increased risk of developing cancer in any of the test groups, an important concern when attempting to preserve or extend telomere length.
Vector-treated mice had increased glucose tolerance, less hair and weight loss. Researchers also saw improved activity and motor coordination than the control group mice of the same age. At 24-months-old, vector-treated mice had mitochondrial integrity in heart and skeletal muscles comparable to non-treated mice a quarter of their age.
Watch this space
In this study, FST and TERT were not combined into a single gene therapy. The question remains whether this combination would be more effective in lifespan extension and healthy aging that the individual vector treatments.
It is certainly worth watching the work that is developed from this study, which holds so much promise for the treatment of age-related conditions, and potentially the extension of healthy human lifespans.
Written by Victoria Lee, Science Writer, Front Line Genomics
Image Credit: Canva
