Longevity Gene Therapy Is the Best Way to Defeat Aging


Схема-для-блога

Gene engineering is the most powerful existing tool for life extension. Mutations in certain genes result in up to 10-fold increase in nematode lifespan and in up to 2-fold increase in a mouse life expectancy. Gene therapy represents a unique tool to transfer achievements of gene engineering into medicine. This approach has already been proven successful for treatment of numerous diseases, in particular those of genetic and multigenic nature. More than 2000 clinical trials have been launched to date.

We propose developing a gene therapy that will radically extend lifespan. Genes that promote longevity of model animals will be used as therapeutic agents. We will manipulate not a single gene, but several aging mechanisms simultaneously. A combination of different approaches may lead to an additive or even a synergistic effect, resulting in a very long life expectancy. For this purpose, an animal will be affected by a set of genes that contribute to longevity. In addition, a gene therapy of all major age-related pathologies will be developed to improve the functioning of individual organs and tissues in old age. As a result, we will develop a comprehensive treatment that will not only dramatically extend lifespan, but will also prevent the decrepitude of the body. Experiments will be conducted in old mice. Thus, in case of success, the developed method of aging treatment can be quickly moved to clinical trials.

The goal of the project is to develop a complex gene therapy that will drastically increase mouse lifespan and prevent tissue pathology in old age, coupled with the safety assessment of the treatment.

Project description

11 genes that are most promising in terms of life extension (table 1) will be used as targets for gene therapy. We will affect both the biological aging mechanisms, common to all the cells of the organism, as well as the primary neuroendocrine center, that regulates the whole organism’s longevity – the hypothalamus. The expression increase or decrease of these genes in animal models was shown to result in boosted longevity. If the increase in expression of a particular gene is necessary for longevity, we will deliver this gene into the body. If, on the other hand, longevity depends on the inhibition of a certain gene’s expression, we will introduce a genetic construct that encodes small RNAs that inhibit the expression of the target gene. Two out of 10 genes have previously been used for gene therapy of aging: the lifespan of mice was increased by 20% (Zhang et al., 2013, Bernardes de Jesus et al., 2012). In addition, we will deliver 8 genes that prevent the individual tissue function disruption in old age. Each of these genes separately has previously been successfully used for gene therapy of one of the age-related diseases in rodent models (table 2).

Therapeutic genes will be introduced into the body using viral vectors – the most powerful method of delivering genetic constructs. This novel therapy that utilizes all the genes simultaniously will be used for radical life extension and for fighting decrepitude. Furthermore, each of the therapeutic genes will be tested individually. All the experiments will be conducted in 2-year old mice.

The experiments will be conducted in the following groups of experimental animals:

  • Simultaneous impact of 11 genes, known to extend life expectancy (table 1) and 8 genes that prevent the development of age-related diseases in various tissues (table 2)
  • Simultaneous impact of 11 genes, known to boost longevity (table 1)
  • Simultaneous impact of 8 genes that prevent the development of age-related pathologies in different tissues (table 2)
  • The impact of each of the 10 genes that extend lifespan, individually (11 groups of animals) (table 1)
  • Exposure to a combination of the 10 most effective geroprotectors
  • Old animals without impact
  • Young animals without impact

First of all, the efficiency of the delivery of therapeutic genes into the cells and duration of gene expression will be tested. If a tissue-specific therapy is needed, the specificity of the therapeutic construct delivery to the target tissue will be studied as well.

All groups of mice will be regularly tested for aging markers, and also the blood and adipose tissue transcriptome, proteome and metabolome will be analyzed. All age-related histological and physiological changes will be studied. Behavioral test will be performed to analyze cognitive ability and locomotor activity in mice. The average and maximum lifespan of mice will be determined. In addition, a detailed study of side effects will be performed. Mice will be compared with old mice of the control group as well as with young mice. 

Table 1. Target genes for life extending gene therapy.

Target gene

The impact on gene expression

Therapeutic effect
Effects on the hypothalamus
NF-кВ Expression inhibition

The inhibition of NF-KB transcription factor causes an increase in hormone production by the hypothalamus with during aging and hypothalamus rejuvenation

UCP2 Overexpression

Uncoupling protein 2 elevates the temperature of the hypothalamus, which is accompanied by a slight decrease in the overall body temperature and increased longevity

Systemic effect on most body cells
TERT Overexpression

The catalytic subunit of the telomerase extends the end regions of chromosomes – the telomeres, which increase the replicative potential of cells and longevity of the body

Repetitive sequences of the genome, encoding retrotransposons Expression inhibition

Inhibiting retrotransposon expression leads reduced genetic instability in old age

CRTC1 Expression inhibition

Inhibiting TOR-kinase, which promotes cell growth and proliferation, leads to increased life expectancy

FOXO3 Overexpression

A transcription factor that triggers stress response and promotes longevity

TFEB Overexpression

A transcription factor that activates autophagy and leads to longevity

ELAVL1 Overexpression

RNA – binding protein HuR stabilizes mRNA of factors regulating the cell cycle. The overexpression of HuR leads to rejuvenation of senescent cells

SIRT6 Overexpression

The overexpression of sirtuin 6 – a NAD + -dependent deacetylase, leads to an increase in life expectancy

AMPK genes Overexpression

AMPK overexpression triggers stress response and promotes longevity

Effect on senescent cells

HSV-TK

Overexpression

Herpes virus thymidine kinase promotes the transformation of a non-toxic prodrug into a toxic product. Thus, exposure to the prodrug induces death of senescent cells

Table 2. Target genes for gene therapy of age-related pathologies. Overexpression of these genes is necessary for the treatment of senile tissue decrepitude.

Target gene Tissue and delivery method

Therapeutic effect

Gene therapy research links
VEGF Systemic delivery into the blood

Vascular endothelial growth factor enhances angiogenesis (blood vessel formation)

Wang et al., 2004
BMP2, BMP7 Systemic delivery into the blood

Bone morphogenetic proteins enhance bone formation and the fracture healing process

Yue et al., 2005; Wang et al., 2008
IL-2 gene Systemic delivery into the blood

A cytokine that stimulates an immune response

Fayad et al., 2004
CREB Hippocampus

A transcription factor that in the hippocampus leads to the improvement of long-term memory formation

Mouravlev et al., 2006
IGF-1 Systemic delivery to the CNS

Insulin-like growth factor-1, whose delivery to the central nervous system (CNS) causes improvement of locomotor activity

Nishida et al., 2011
ecSOD Penis

Extracellular superoxide dismutase improves erectile function by reducing oxidative stress

Bivalacqua et al., 2003
GDNF Hypothalamus

Glial-derived neurotrophic factor that reduces obesity when delivered to the hypothalamus

Tumer et al., 2006
PVALB Heart A Ca2+- binding protein, that causes improvement of the hearts diastolic function Schmidt et al., 2005

Project authors: Anastasia Shubina, Timofey Glinin, Mikhail Batin, Maria Konovalenko and Alexey Moskalev.

Literature

  1. Bernardes de Jesus B., Vera E., Schneeberger K., Tejera A.M., Ayuso E., Bosch F., Blasco M.A. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer // EMBO Mol Med. – 2012. – .v.4(8). – P.691-704.
  2. Bivalacqua T.J., Armstrong J.S., Biggerstaff J., Abdel-Mageed A.B., Kadowitz P.J., Hellstrom W.J., Champion H.C. Gene transfer of extracellular SOD to the penis reduces O2-* and improves erectile function in aged rats // Am J Physiol Heart Circ Physiol. – 2003. – v.284(4). – H1408-21.
  3. Fayad R., Zhang H., Quinn D., Huang Y., Qiao L. Oral administration with papillomavirus pseudovirus encoding IL-2 fully restores mucosal and systemic immune responses to vaccinations in aged mice // J Immunol. – 2004. – v.173(4). –P.2692-8.
  4. Mouravlev A., Dunning J., Young D., During M.J. Somatic gene transfer of cAMP response element-binding protein attenuates memory impairment in aging rats // Proc Natl Acad Sci U S A. – 2006. – v.103(12). – P.4705-10.
  5. Nishida F., Morel G.R., Hereñú C.B., Schwerdt J.I., Goya R.G., Portiansky E.L. Restorative effect of intracerebroventricular insulin-like growth factor-I gene therapy on motor performance in aging rats // Neuroscience. – 2011. – v.177. – P.195-206.
  6. Schmidt U., Zhu X., Lebeche D., Huq F., Guerrero J.L., Hajjar R.J. In vivo gene transfer of parvalbumin improves diastolic function in aged rat hearts // Cardiovasc Res. – 2005. – v.66(2). – P.318-23.
  7. Tümer N., Scarpace P.J., Dogan M.D., Broxson C.S., Matheny M., Yurek D.M., Peden C.S., Burger C., Muzyczka N., Mandel R.J. Hypothalamic rAAV-mediated GDNF gene delivery ameliorates age-related obesity // Neurobiol Aging. – 2006. – v.27(3). – P.459-70.
  8. Wang H., Keiser J.A., Olszewski B., Rosebury W., Robertson A., Kovesdi I., Gordon D. Delayed angiogenesis in aging rats and therapeutic effect of adenoviral gene transfer of VEGF // Int J Mol Med. – 2004. – v.13(4). – P.581-7.
  9. Wang Q-L., Han Q-L., Kang J., Gou S.-H., Wang L.-Zh. Polyethylenimine-mediated BMP-7 gene transfection promotes fracture healing in elderly rats // Academic Journal of Second Military Medical University. – 2008. – v.28(5). – P.514-518.
  10. Yue B., Lu B., Dai K.R., Zhang X.L., Yu C.F., Lou J.R., Tang T.T. BMP2 gene therapy on the repair of bone defects of aged rats // Calcif Tissue Int. – 2005. – v.77(6). – P.395-403.
  11. Zhang G., Li J., Purkayastha S., Tang Y., Zhang H., Yin Y., Li B., Liu G., Cai D. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH // Nature. – 2013. – v.497(7448). – P.211-6.

22 Comments

Filed under Research project

22 responses to “Longevity Gene Therapy Is the Best Way to Defeat Aging

  1. That is very interesting Maria, thank you for sharing. There is one thing I am curious about. You wrote that “If the increase in expression of a particular gene is necessary for longevity, we will deliver this gene into the body. If, on the other hand, longevity depends on the inhibition of a certain gene’s expression, we will introduce a genetic construct that encodes small RNAs that inhibit the expression of the target gene.” That makes sense, but what is the actual mechanism by which the genes or gene constructs would be delivered into the body? Does the gene or gene construct then somehow automatically actually end up in the places where it needs to be, or how does one actually get the genes into the cells that need them? I presume oral insertion of the genes (in food or drink) would not work since they would just get digested and/or eliminated, but does injecting them into the blood work, or do they need to be directly injected into specific cells? If they need to be injected into specific cells, how can they have a major impact, given the sheer number of cells in a human being (or even in any single organ, or even in a mouse)? Is it logistically realistic to inject genes into a sufficiently large percentage of cells for it to make a difference? Thank you for your research and for sharing it!

    • I am also wondering whether use of the “viral vector” method for delivering genes would have any negative side effects resulting from the fact that cells need to become infected by the carrier virus in order to receive the genes. I suppose the tests will examine the issue of whether the viruses are truly harmless.

  2. This is a very exciting project. I am very concerned though that medical ethicists will try to obstruct such augmentative gene therapy due to the fears that the human genome is somehow sacrosanct, and progeny could be affected in unknown (unknowable) adverse ways (due to the lack of “time tested” evolutionary evidence).

    The same objection has been voiced about GMO agriculture, but fears of “polluting” or “corrupting” animal or plant DNA are not as vehement as that same fear that a genetic “time bomb” could be introduced into human lineage.

    Don’t get me wrong – I am all for augmentative gene therapy in humans, but maybe the first recipients ought to be sterilized to blunt such criticism. I personally have had a vasectomy (TMI – sorry), so would be a good candidate for beta testing such an augmentative gene therapy treatment, and would be honored if you would put me on any waiting list.

    One other thing: instead of just one augmentative gene therapy doing so many things at once, is it safer to do one thing at a time. The unforeseen interaction between different genetic alterations could be very very complicated. Just askin.

    • I don’t think the sterilization will be necessary. Gene therapy can be conditional, meaning it can be switched on and off by a drug. This has already been done. Also, the adeno-associated viruses do not integrate into the genome, so there is expression of the delivered protein, but it’s temporary. So I wouldn’t worry too much about the anti-gene therapy lobby. If people start talking about this experiment I will think of it as a good thing, because right now nobody has heard about it except a few people who read my blog. Whereas millions of people should be aware of the concept, because their lives depend on the results of this experiment.

  3. Yes this is a great concept and one I have been pondering for many years from my work in targeting enzymes using targeted viral vectors for activation of masked chemical regulators “Prodrugs” to specific target cells and cellular compartments to the use of a “Trojan horse” viral delivery mechanism utilizes well known viruses that integrate into the genome and regulate cell proliferation and apoptosis. Understanding the underlying biology of viral integration allows us to use this as a mechanism to enable exactly what you are proposing here. This is very achievable and would not take too long to make work in humans. Would like very much to facilitate this becoming a reality!!

  4. Dmitry Dzhagarov

    The body is very complex machine and difficult to predict the consequences. I would suggest not a complex cocktail of genes, but overexpression of one – two.   eg : Nrf2 & FOXO3 or ATF4 & FOXO3

  5. Hi Maria, Who will do this research, what are the timelines/milestones, how is it being funded?

    thanks,
    Dave Gobel

  6. The depths of the study and research it has taken to break down genome codes of the gene’s and their purpose is amazing.. Yet, again I must say, it is not the gene’s, it is what has made its way into the Gene’s…. Respect

  7. Amazingly insightful article/post I must add also.. Very well explained and broken down for easy comprehension …. Respect

  8. Alice

    The project is perfect! The idea to combine different therapies is so obvious, so I’m suprised that nobody did it before..

  9. I really hope this moves from idea to funding to experiment within my lifetime!
    As for the anti-longevity lobby, they are really hard to understand, except as general anti-progress folks. One only has to ask: Is the world a better place today because more people live to be 80 instead of 40? The answer is a resounding “Yes!” Therefore, there is no reason to believe it will not be an even better place if people can live longer, healthier lives to 160 instead of 80, and so on.
    The “population pressure” arguments would be so long in coming, and in any case, have much more to do with resource overuse and poor economic models than with sheer numbers of humans (the average Park Avenue resident uses 30-50X the resources of the average Ethiopian, and yet, no one talks about having more Ethiopians and fewer Park Avenue humans).
    Good luck with this. I can’t wait!

  10. Pingback: Longevity Gene Therapy Is the Best Way to Defeat Aging | limitless life

  11. Steve H

    Bioviva is moving into testing gene therapy in humans they are doing TERT and a Myostatin inhibitor combination as their first test therapy. Fingers crossed it brings the results we need.

    • We have found the mutators that causes gene mutation and ageing.. http://adamandevewordresearch.blogspot.com/ … Respect

    • “Bioviva is moving into testing gene therapy in humans they are doing TERT and a Myostatin inhibitor combination as their first test therapy”. But inactivation of myostatin to increase muscle size did not
      show improved muscle strength or function. Do not forget also that this strategy must be cautious because of the oncogenic potential of TERT-transformed cells & their ability to enhance already established cancers.TERT is better to combine with Senolytics to remove oncogenic cells.

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