Mouse age reversal – very interesting but misrepresented research

A longevity news story breaking today was widely published in the world press.  Some of the 123 headlines listed on Google are Ageing Process “reversed” in mice, Die hard: Scientists reverse aging in mice,  Scientists unlock secret of eternal youth,  Secret to eternal youth ‘found’, Harvard scientists reverse aging in mice, Virility, Mental Ability Restored in Aged Mice in Gene Study,Nature Says, Science Makes Old Mice Young Again, Scientists Find Fountain of Youth … in Mice, Harvard University Doctor Turns Back Time on Aging: Will an Anti-Aging Pill Be .., Enzyme Reverses Aging in Mice and The Curious Case of the Backwardly Aging Mouse.

I think the research reported is quite important though these headlines sensationalize and misrepresent that research.  I comment here both on the research and on the press coverage it received.

The publication that initiated this press flurry is a 28 November online publication that appeared in Nature Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.  “An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses1.  Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2+ neural progenitors, Dcx+ newborn neurons, and Olig2+ oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons2, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk and the marked reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.”

So, mice were genetically engineered to be born with knocked-out telomerase genes and these mice aged in an accelerated fashion  They eventually exhibited most or all the degenerative conditions known to be associated with aging.  Such effects have been observed for many years.  The new discovery is that reactivation of telomerase in these mice reverses many of the phenomena of aging and, in effect, makes these mice younger again.  This is an extremely important discovery because it strongly suggests that a single intervention can reverse the multiple deleterious manifestations of aging which have always been thought to be permanent and, once occurred, irreversible.  At least this seems to be true for aging induced by telomerase deficiency.  To me it comes close to being a mind-boggling proof-of-concept that aging can be reversed, establishing that aging is a two-way street.  It is also additional evidence that aging is not just due to accumulation of random damage due to wear-and tear.  It would be impossible to repair so many and so radically different forms of random damage with a single intervention. 

The writeup in Nature News is more plain-spoken. “ — When mice are engineered to lack telomerase completely, their telomeres progressively shorten over several generations. These animals age much faster than normal mice — they are barely fertile and suffer from age-related conditions such as osteoporosis, diabetes and neurodegeneration. They also die young. “If you look at all those data together, you walk away with the idea that the loss of telomerase could be a very important instigator of the ageing process,” says DePinho (Ronald DePinho, an author of the research publication and a cancer geneticist at the Dana-Farber Cancer Institute and Harvard Medical School). — To find out if these dramatic effects are reversible, DePinho’s team engineered mice such that the inactivated telomerase could be switched back on by feeding the mice a chemical called 4-OHT. The researchers allowed the mice to grow to adulthood without the enzyme, then reactivated it for a month. They assessed the health of the mice another month later. — “What really caught us by surprise was the dramatic reversal of the effects we saw in these animals,” says DePinho. He describes the outcome as “a near ‘Ponce de Leon’ effect” — a reference to the Spanish explorer Juan Ponce de Leon, who went in search of the mythical Fountain of Youth. Shrivelled testes grew back to normal and the animals regained their fertility. Other organs, such as the spleen, liver and intestines, recuperated from their degenerated state. — The one-month pulse of telomerase also reversed effects of ageing in the brain. Mice with restored telomerase activity had noticeably larger brains than animals still lacking the enzyme, and neural progenitor cells, which produce new neurons and supporting brain cells, started working again. — “It gives us a sense that there’s a point of return for age-associated disorders,” says DePinho. Drugs that ramp up telomerase activity are worth pursuing as a potential treatment for rare disorders characterized by premature ageing, he says, and perhaps even for more common age-related conditions. – “

Let me turn to the sensationalism in the press reporting for a moment.  If you have read my recent blog post When reading press releases and newspaper articles about research discoveries, beware!  then you know I am sensitive to misrepresentation of research results in headlines.   I hate to be nitpicking but most of the press reports for this research do not make clear:

1.     The study shows only that accelerated aging from one cause can be reversed, that cause being lack of telomerase expression.  We know that many causes can accelerate apparent aging (like exposure to radiation and some chemicals) but we do not know yet whether aging from such causes can be reversed.  And we do not know if natural aging, however that comes about, can be reversed.  I hope and suspect that aging-is-aging and aging from all causes can be reversed, but as a scientist I don’t know yet that this is true.  

2.     The apparent age reversal observed was not in normal mice who aged normally.  It was in mice genetically engineered not to have a natural feature, an active telomerase gene, who age (or do something very much like aging) prematurely.  The age-reversal was initiated by restoring what had been taken away, natural telomerase production.  We do not know if the age reversal would work in normally aged mice let alone in normally-aged humans.   

3.     Despite the fact that telomerase-deficient mice age more rapidly, neither this work nor any other research I know about establishes that telomere-lengths are critical for limiting normal lifespans in either mice or humans.  It was not reported that the mutant mice who underwent age-reversal lived longer than normal mice.  There is no indication that extended lifespan let alone eternal youth was involved despite the headlines claiming it. 

4.     The genetic-engineering approach to turning the telomerase genes back on in the mutant mice can’t be used in humans since any genetic engineering of humans is taboo.

“Harrison (David Harrison, who researches ageing at the Jackson Laboratory in Bar Harbor, Maine) also questions whether mice lacking telomerase are a good model for human ageing. “They are not studying normal ageing, but ageing in mice made grossly abnormal,” he says. Tom Kirkwood, who directs the Institute for Ageing and Health at Newcastle University, UK, agrees, pointing out that telomere erosion “is surely not the only, or even dominant, cause” of ageing in humans(ref).”

So, while this research is important and very encouraging from the viewpoint of life extension, it is not at all clear that it will lead to life-extending interventions in humans.  I agree with DePinho who “says he recognizes that there is more to ageing than shortened telomeres, particularly late in life, but argues that telomerase therapy could one day be combined with other therapies that target the biochemical pathways of ageing. “This may be one of several things you need to do in order to extend lifespan and extend healthy living,” he says(ref).”

For background you can read about the Telomere Shortening and Damage theory of aging in my treatise.  For updates on recent research on telomerase, you can see my recent blog entries:

* Telomere lengths, Part 3: Selected current research on telomere-related signaling,

* Telomere lengths, Part 2: Lifestyle, dietary, and other factors associated with telomere shortening and lengthening, and

* Telomere lengths, Part 1: Telomere lengths, cancers and disease processes.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com. Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.
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12 Responses to Mouse age reversal – very interesting but misrepresented research

  1. Res says:

    //To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. //

    what does this mean?

    http://en.wikipedia.org/wiki/Tamoxifen

    this is that
    This is currently provided to the breast cancer patients.

  2. Mike says:

    Telomere shortening IS a major cause of ageing in humans,
    but not mice (who have extremely long telomeres compared to humans).Consequently it is useless to do telomere experiments on “normal” mice,the only way to use mice is for this type of experiment to be performed on telomere deficient mice.

    The take home message is that the re-lenghtening of telomeres can fix many of the problems chronic telomere shortning causes.It is true that it wont fix all of Aubreys 7 problems of human aging,but re-lenghtening of telomeres will go a very long way to repairing most diseases suffered by aging humans.

    Your somal cells will live longer, your tissue specific stem cells whose regenerative capacity declines with their declining telomere lenghts will be viable for a much longer period of time(they decline because they are only partially restored after cell division).

    Senecent cells adversly alter thier local enviroments for non senecent cells, preventing cells from reaching senecence for a longer period will greatly aid your bodies ability to regenerate. Also your aging immune system functionality would be partially restored allowing senecent and cancerous cells to be better cleared from the body.

    On the subject of cancer there is currently no data to suggest that re-lenghtening telomeres will increase cancer rates, because cancer cells have extremely short telomeres and they remain extremely short even though their telomeres have had some re-lenghtening.

    My last and most important point is that significant re-lenghtening telomeres changes histone patterns and gene expression to that of a cell in a much younger state and that change alone will probably greatly decrease the chances of cancer and other degenerative diseases.

  3. admin says:

    Mike

    Thanks for your comments. I remark on them here.

    M Telomere shortening IS a major cause of ageing in humans,
    but not mice (who have extremely long telomeres compared to humans).Consequently it is useless to do telomere experiments on “normal” mice,the only way to use mice is for this type of experiment to be performed on telomere deficient mice.

    VG You are right about mice but many researchers, including some most involved with telomerase, today see telomere shortening as a manifestation of the aging process, except in rare cases not the cause.

    M The take home message is that the re-lenghtening of telomeres can fix many of the problems chronic telomere shortning causes.

    VG Right. If the problem is too-short telomeres to start with then lengthening can apparently reverse a wide variety of aging symptoms.

    M It is true that it wont fix all of Aubreys 7 problems of human aging,but re-lenghtening of telomeres will go a very long way to repairing most diseases suffered by aging humans.

    VG I don’t think there is evidence supporting that statement because the telomere shortening associated with a disease is caused by the disease process that creates all kinds of other havoc and lengthening the telomeres won’t cure the disease.

    M Your somal cells will live longer, your tissue specific stem cells whose regenerative capacity declines with their declining telomere lenghts will be viable for a much longer period of time(they decline because they are only partially restored after cell division).

    VG Your statement about somal cells is a wonderful speculation that highly motivated me when I seriously got onto longevity research years ago. Unfortunately, I don’t think there is research evidence that this happens in-vivo. There does seem to be evidence that age-related decline in adult stem cell differentiation is associated with senescence of such cells and that telomerase expression can promote stem cell differentiation through a different mechanism than telomere lengthening. If there is a key role for enhancing telomerase expression to enhance normal longevity, I think it will be in enhancing the vitality of adult stem cells.

    M Senecent cells adversly alter thier local enviroments for non senecent cells, preventing cells from reaching senecence for a longer period will greatly aid your bodies ability to regenerate.

    VG True, true. However, the onset of cell senescence is a very complicated process and it is unclear that exogenous promotion of telomerase expression can forestall cell senescence.

    M Also your aging immune system functionality would be partially restored allowing senecent and cancerous cells to be better cleared from the body.

    VG There have been some studies indicating that the replicative lives of key immune cells can be extended by enhancing telomerase expression in the case of HIV. I do not know if this statement as related to people with normal immunce systems is supported by research studies, however.

    Remember that in the experiment reported in this blog entry, the telomerase-comprimised mice experiencing what seemed to be age reversal because of telomerase re-expression did not live any longer than their normal counterpart mice.

    M On the subject of cancer there is currently no data to suggest that re-lenghtening telomeres will increase cancer rates, because cancer cells have extremely short telomeres and they remain extremely short even though their telomeres have had some re-lenghtening.

    VG I agree with that. However the worry lingers on the part of many researchers and it will take epidemiological studies to prove the point. Also I am unclear what you mean when you talk about “re-lenghtening telomeres.” How are you proposing to do that? Using a substance like cycloastragenol that works weakly if at all?

    M My last and most important point is that significant re-lenghtening telomeres changes histone patterns and gene expression to that of a cell in a much younger state and that change alone will probably greatly decrease the chances of cancer and other degenerative diseases.

    VG This is a very very interesting statement and important if valid. Can you point me to any research studies establishing this point about re-lenghtening telomeres changing histome patterns and gene expression?

  4. What Activates Telomerase ? Whether you happen to be a human being or a mouse, the most logical and effective way to increase telomerase activity, lengthen the telomeres and reverse aging is with the human bioidentic­al hormone, 17-Beta-Es­tradiol, also known as estrogen. In 1999, Kyo demonstrat­ed that 17-Beta-Es­tradiol activates telomerase via direct and indirect effects on the hTERT promoter region. This was confirmed in 2000 by Silvia Misiti and again in 2009 by Rodrigo T. Calado from the NIH A recent December 2010 study from Imanishi from Japan showed that 17-Beta-Es­tradiol (estrogen) augments telomerase activity, thereby accelerati­ng recovery after injury and reducing the effects of aging (reducing senescence­). If this isn’t a descriptio­n of anti-aging effects, I don’t know what is.An important study in Circulatio­n 2006 found that 17-Beta Estradiol enhances recovery after heart attacks by augmenting incorporat­ion of endothelia­l stem cells and inducing new collateral vessels in the ischemic myocardium­. This beneficial effect is related to telomerase activation of the Endothelia­l Progentior cells.

    For more see:http://jef­freydach.c­om/2010/12­/03/anti-a­ging-break­through-wi­th-telomer­ase-knocko­ut-mice-by­-jeffrey-d­ach-md.asp­xjeffrey dach md

  5. admin says:

    Jeffrey Dach:

    Thank you for your comment. I have not heard of use of 17-Beta-Es­tradiol to activate telomerase production but your comment certainly has hooked me. Up to this point I have paid no special attention to estrogen. I will look at your site and see if I can dig up the studies you mentioned and quite possibly produce a new blog entry on the topic.

    Vince

  6. eric25001 says:

    Yes
    Much hype with little substance. And then an article from UCSF that seems reasonable and involves a drug in use that seems to hold much promise. I was not sure where to post the comment and link so that it would not A) get lost or B) Be misfiled or in the wrong category but here is where I post it ==

    UCSF “fountain of youth” pill could restore aging immune system

    LINK ==> http://news.ucsf.edu/releases/ucsf-fountain-of-youth-pill-could-restore-aging-immune-system/

    UCSF researchers have identified an existing medication that restores key elements of the immune system that, when out of balance, lead to a steady decline in immunity and health as people age.

    The team found that extremely low doses of the drug lenalidomide can stimulate the body’s immune-cell protein factories, which decrease production during aging, and rebalance the levels of several key cytokines – immune proteins that either attack viruses and bacteria or cause inflammation that leads to an overall decline in health.

    The initial study, which was designed to define the dose range of such a therapy in a group of 13 patients, could lead to a daily pill to boost immunity in the elderly, the researchers said. Data will appear in the January issue of the journal Clinical Immunology, and can be found online at http://www.elsevier.com/locate/yclim.

    The identification of a drug to reverse the immunological decline in aging, known as immunosenescence, is the culmination of years of research by Edward J. Goetzl, MD, at UCSF and the National Institute on Aging, into how cytokine levels change as people age, how that varies by gender, and which changes dictate whether someone will be healthy into their 90s or begin a downward cycle of decline starting in middle age.

    “No one’s really talking about longevity and lifespan now, but about ‘health span,’” said Goetzl, director of UCSF Allergy and Immunology Research, which focuses on developing new diagnostics and treatments for allergic and immunological diseases.

    “If, at age 50, your cytokine levels are the same as they were at 25, you’ll probably stay healthy as you age,” he said. “But if they’re heading downhill, we need to do something about it. If you could take a low-dosage pill with no side effects, wouldn’t you do it?”

    In 2009, Goetzl had studied a group of 50 elderly adults through the National Institute on Aging, examining their levels of key cytokines – Interleukin (IL)-2, IFN-gamma and IL-17 – and discovered that truly healthy 70-80 year old women had the same levels of those as did healthy 20 year olds.

    However, some elderly men and frail women who showed increased levels of inflammatory diseases and weakened defenses against infections tended to have lower levels of the first two cytokines, which are protective, and higher levels of inflammatory cytokines. That imbalance, the researchers found, began in late middle age.

    They then set out to find a drug that could raise IL-2 and IFN-gamma and either have no effect on IL-17 or lower it.

    “We now had a profile – in humans – that we could take to test tubes to say, ‘Does this drug have a desirable effect?’” Goetzl said. “Our job was to find a therapy that not only works, but does so at a dose range with no side effects.”

    The team focused on three classes of drugs, among them the one that includes lenalidomide – a derivative of thalidomide – which is undergoing a renaissance, Goetzl said.

    First introduced in the late 1950s as a sedative, thalidomide was never approved in the United States, but was withdrawn from the world market in 1961 after causing severe birth defects in infants whose mothers took the drug to reduce nausea during pregnancy.

    In recent years, however, lenalidomide has been found to be an effective co-therapy for some cancers, particularly multiple myeloma and kidney tumors, as well as leprosy, at doses of 5 mg to 20 mg per day. Those cancers are tied to a drop in IL-2, the main cytokine that Goetzl’s team had linked to declines in aging immune systems.

    In this study, the team tested the drug in healthy seniors, each of whom were matched in race, gender and national origin to a healthy young adult participant. They found that extremely low levels of lenalidomide – 0.1 μM – optimally stimulated IL-2 production in the young people (21-40 years) roughly sevenfold, but stimulated IL-2 production in patients over age 65 by 120-fold, restoring them to youthful levels for up to five days. At that dosage, the drug also increased IFN-gamma up to six fold in the elderly patients, without suppressing IL-17 generation.

    The researchers also found that lenalidomide had many other beneficial effects on the elderly participants’ T cells, including better migration throughout the body, more efficient patrolling activity and longer survival after defending the body against an infection.

    The team plans to begin larger-scale clinical trials in 2011 to test the drug’s effectiveness and hopes for broader availability within a few years.

    The research was supported by a grant from the Kenneth Rainin Foundation and by the Intramural Research Program of the National Institute on Aging. The authors declare no conflicts of interest.

    The first author on the paper is Mei-Chuan Huang, who, along with Goetzl and co-author Janice B. Schwartz, is from the UCSF departments of Microbiology-Immunology and of Medicine. Co-authors are Nigel Greig, Weiming Luo, David Tweedie, Dan Longo, Luigi Ferrucci and William B. Ershler, all from the National Institute on Aging, of the National Institutes of Health, in Baltimore.

    UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

    ###

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