Telomerase and Follistatin Gene Therapies Delivered via Cytomegalovirus Extend Life in Mice
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.
There is skepticism around the results of this study:
" This mouse study makes some remarkable claims. In summary, they report that viral introduction of TERT or FST (genes that extend telomere length and boost muscle development, respectively) extend the mouse lifespan in a safe manner.
But to me the data seem almost too good to be true.
The reported benefits are huge in magnitude. It is surprising as well that they report no side effects. Note that TERT overexpression or changes in other factors that impact telomere biology are common features of many human cancers.
Further, I don't understand how IP injection and nasal administration of a gene therapy would work so similarly and why would nasal administration yield results all over the body? It gets into the bloodstream quickly?
Adding to the mystery is why boosting TERT and FST produced such similar results. These are very different genes encoding totally distinct kinds of proteins.
I think there's reason for some skepticism here and I'm not alone as check out this Endpoints piece."
Elizabeth Parrish... lulz!
This is just one experiment, and I agree that we would need more like it to confirm the excellent results. A big part of their purpose here seems to be using cytomegalovirus as their gene vector. I understand that CML evades a lot of immune system attacks--is this one of the reasons they are working with it?
I am no expert, but I think it is not that hard to extend the lifespan of short lived animals. As for nasal administration, well, people snort cocaine, and that definitely gets into the bloodstream just fine.
I did not see any comments regarding muscle growth in the animals. I would like to hear more on that, since muscle growth would be an undeniable and very visible sign the Follastatin genes were delivered and are functioning.
Successful followup experiments from other labs confirming these results would be wonderful news.
'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. '
Even if one wants to take Elizabeth Parrish's 'research' seriously, this is nothing to write home about. The effect size in MICE is just in range of simpler interventions. Even something crude like fasting extends lifespan in mice by 28% (https://www.nih.gov/news-events/nih-research-matters/fasting-increases-health-lifespan-male-mice).
So what I see here is utter failure of her 'gene therapy' to do significantly better than the already known life extension interventions. Consider David Sinclair's claim that he has a 6! year old mouse in one of his labs...
Why does anyone take still take this woman seriously? And why in the name of God does George Church even associate with her??
Claim to take gene therapy, never disclose any real results that mean anything, ask people to pay millions of $$$ for therapy, and then try to do slight of hand with this type of mouse data paper.
What a sad state of affairs
@Reason As HCMV is so prevalent in the population, most people have a strong Tcell immunity against most of his proteins. This makes this a poor choice for a gene therapy vector. The transcduced cells would be eliminated quickly and the desired effect won't be reached. Sadly it sounds like a waste of time...
Unbelievably negative reaction to this paper, which I doubt anyone here has actually even bothered to read. There are certainly some shortcomings to the paper, like small groups and only sacrificing a mouse from each group at one timepoint - but all in all it does advance our knowledge.