Upregulation of telomerase expression and, separately, follistatin expression have been shown to extend life in mice. In recent news, researchers report a novel approach to delivering these two genes via gene therapy, making use of cytomegalovirus (CMV) as a vector. CMV is actually a major threat to human health, and might be responsible for a great deal of the age-related decline of the immune system. Near everyone is infected by the time old age rolls around. Nonetheless, one can develop viral vectors in which replication (and thus any threat of infection) is disabled, and these are widely used as tools in research and development.
Cytomegalovirus is most analogous to adeno-associated virus (AAV) in terms of how it works to make a cell produce desired proteins without introducing new DNA into the genome. It appears to be good at delivering its cargo to immune cells in particular, which may go some way towards explaining positive outcomes for telomerase in the study noted below. Immune system function is very important in aging, and immune cells replicate dramatically in response to infection. An increased capacity to replicate may do more good in the immune system than anywhere else in the body.
Telomerase upregulation extends life via a general boost to cell function, and probably stem cell function in particular. Telomerase acts to extend telomeres, which shorten with each cell division, enabling cells to push back the Hayflick limit in order to replicate and work for longer. In mice at least, the risk of cancer due to damaged cells remaining active appears more than compensated for by improved function in the immune system or other anti-cancer mechanisms. Cancer is reduced, but exactly why this is the case is still poorly explored. It is also possible that telomerase has meaningful effects on mitochondrial health in old age via its less well explored functions in the cell. No protein has just one task in the body; evolution likes reuse.
Follistatin is an inhibitor of myostatin, which in turn suppresses muscle growth. The effect of follistatin upregulation is thus a sizable growth in muscle mass, though it also reduces inflammation, fat tissue mass, and infiltration of fat into muscle tissue, among other beneficial shifts in metabolism. Mice engineered to overexpress follistatin or lacking myostatin are very heavily muscled, and as shown in the research here, live longer than their unmodified peers.
New intranasal and injectable gene therapy for healthy life extension
How to achieve healthy longevity has remained a challenging subject in biomedical science. It has been well established that aging is associated with a reduction in telomere repeat elements at the ends of chromosomes, which in part results from insufficient telomerase activity. Importantly, the biological functions of the telomerase complex rely on telomerase reverse transcriptase (TERT). TERT plays a major role in telomerase activation, and telomerase lengthens the telomere DNA. Because telomerase supports cell proliferation and division by reducing the erosion of chromosomal ends in mitotic cells, animals deficient in TERT have shorter telomeres and shorter life spans. Recent studies on animal models have shown the therapeutic efficacy of TERT in increasing healthy longevity and reversing the aging process.
The follistatin (FST) gene encodes a monomeric secretory protein that is expressed in nearly all mammalian tissues. In muscle cells, FST functions as a negative regulator of myostatin, a myogenesis inhibitory signal protein. FST overexpression is known to increase skeletal muscle mass in transgenic mice by 194% to 327% by neutralizing the effects of various TGF-β ligands involved in muscle fiber break-down, including myostatin and activin inhibition complex. These findings strongly implicate the therapeutic potential of FST in the treatment of muscular dystrophy and muscle loss caused by aging or microgravity. Thus, TERT and FST are among prime candidates for gene therapy aimed to improve healthy life spans.
As more longevity-supporting factors are discovered, it is of interest to determine potential large capacity vectors for delivering multiple genes simultaneously. Unlike AAV, lentiviruses, or other viral vectors used for gene delivery, cytomegaloviruses have a large genome size and unique ability to incorporate multiple genes. Cytomegaloviruses also do not integrate their DNA into the host genome during the infection cycle, thus mitigating the risk of insertional mutagenesis. They also do not elicit symptomatic immune reactions in most healthy hosts. Notably, the CMV vector does not invoke genome instability and has not been identified to cause malignancies. Human CMV (HCMV) has been proven a safe delivery vector for expressing therapeutic proteins in human clinical trials.
Using mouse cytomegalovirus (MCMV) as a viral vector, we examined the therapeutic potential of TERT and FST gene therapy to offset biological aging in a mouse model. We found that the mouse cytomegalovirus (MCMV) carrying exogenous TERT or FST extended median lifespan by 41.4% and 32.5%, respectively. This is the first report of CMV being used successfully as both an intranasal and injectable gene therapy system to extend longevity. Treatment significantly improved glucose tolerance, physical performance, and prevented loss of body mass and alopecia. Telomere shortening seen with aging was ameliorated by TERT, and mitochondrial structure deterioration was halted in both treatments. Intranasal and injectable preparations performed equally well in safely and efficiently delivering gene therapy to multiple organs, with long-lasting benefits and without carcinogenicity or unwanted side effects. Translating this research to humans could have significant benefits associated with increased health span.
View the full article at FightAging
