Biologists are, at long last, beginning to understand the molecular processes responsible for aging in complex (multicellular) organisms – and to investigate ways to counteract these processes. We discussed one line of research in this recent article about a particular sirtuin (SIRT3) that helps relieve oxidative stress that can lead to DNA damage, which generally leads, in turn, to cell senescence or death.
While oxidative stress is certainly a significant factor in aging, possibly the most significant, there are others. One of these is the limitation on a cell's ability to undergo cell division in order to produce new cells of the same type. This is especially important in tissues that regularly need to regenerate, such as skin and intestinal tissue. Everyone now knows about telomeres, whose main function is to constitute protective end caps on chromosomes. The limitation on number of cell divisions happens since about 100 base pairs are lost from telomeres during each cell division. When telomeres eventually become too short signals that are similar to those associated with other kinds of DNA damage shut down a cell's ability to divide further. This mechanism indirectly helps mitigate the risks of DNA damage that are present every time a cell divides – an inherently tricky process.
However, this limitation on cell division isn't acceptable during embryonic development, when an organism's cell count is doubling most rapidly. So evolution has provided an enzyme – telomerase – that can rebuild telomeres, but is most active only during embryonic development. Except, of course, in cells that have become cancerous, where the ability to divide without limit is the name of the game. We discussed telomeres and telomerase in some detail a little over a year ago in this article, so you can go there for more.
Because of the risk of cancer, it seems imprudent to reactivate telomerase for the long term within an organism, especially in long-lived animals such as humans. (In animals like mice, which live fast and die young, it's a different matter. Telomerase may remain somewhat active in mice during adulthood. (Mentioned here.)) But what if it were possible to reactivate telomerase for a relatively short period of time (compared to the whole lifespan)... might that provide an opportunity to rebuild telomeres to some extent? Even better, might that reverse, at least to some extent, the ravages of aging?
We now have some research that seems to provide a fairly unambiguous affirmative answer... in a rather special case: Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.
But didn't we just say that mice may retain telomerase activity throughout their lives? Yes, however it's a relatively simple matter to "knock out" the main telomerase gene in mice (Tert). When that's done the resulting strain of knock-out mice – after several generations – have shortened lifespans and a general phenotype of age-related debilities, as one would expect. (The first few generations apparently still have sufficiently long teleomeres.)
Unfortunately, that's not a good enough model, since without a Tert gene, the organism has no way to manufacture telomerase. Simply giving the knock-out mice repeated infusions of telomerase is not a good way to ensure uniform distribution of the enzyme to all of the organism's cells. What to do? The experimenters came up with a rather clever solution. Normally the way that telomerase is activated in cells is by means of an "estrogen receptor" (ER), to which a form of the hormone estrogen (17β-estradiol to be precise) can bind and enable transcription of Tert. This ER can be tweaked so that estrogen binds to it only in the presence of another chemical, 4-hydroxytamoxifen (4-OHT).
A special form of the Tert gene that includes this special ER can be "knocked-in" to the mouse germline. It then turns out that 4-OHT can be efficaciously supplied to a TERT-ER mouse (in the form of a time-release subcutaneous pellet) to turn telomerase expression on and off at the experimenter's will. With that technology in place, the researchers were then able to perform a series of experiments demonstrating, in these special mice, that a month-long burst of telomerase could actually reverse a number of the ill effects of telomerase deprivation.
The first step was to show that without 4-OHT the TERT-ER mice (after a few generations) had many of the same problems, in the same degree, as later generations of knock-out mice that lacked Tert entirely. The TERT-ER mice (all of which were male) showed no signs of telomerase activity. Tissues in highly proliferative organs such as testes, spleen, and intestines showed notable atrophy. Lifespan of TERT-ER mice was about half that of normal ("wild type") mice.
The first test to investigate the effects of telomerase reactivation by means of 4-OHT was done in vitro. Fibroblast cells from TERT-ER mice were cultured and found to be essentially senescent and not undergoing cell cycles. But when the cells were placed in media containing 4-OHT, teleomerase was reactivated, telomeres lengthened, and cell proliferation resumed.
Some TERT-ER mice were then given a 4-week treatment of 4-OHT (subcutaneous pellets). At the end of that treatment there was a marked reversal of the degeneration that has occurred in testes, spleen, liver, and intestinal tissues, as well as resumption of sperm production. Survival time of these treated mice also increased. At the same time, 4-OHT had no effects on control mice that weren't lacking in telomerase and didn't have tissue degeneration.
Noteworthy results were obtained from tests to assess nervous system condition. Proliferation of neural progenitor cells was found to resume in TERT-ER mice treated with 4-OHT. Normal numbers of mature oligodendrocytes reappeared. Lastly, high-level neurological functions were restored, as indicated by resumption of nearly normal olfactory sensitivity.
An interesting conclusion that can be drawn from the neurological results is that neural progenitor cells probably survive loss of telomeres, so that they can rebuild neural cell populations if telomeres are repaired.
The really interesting question, of course, is the extent to which these results may apply, in some form, to humans. Unfortunately, there are a number of reasons to be skeptical. For one thing, telomere shortening is only one factor, and quite possibly not the main one, in human aging. Aging can be thought of as a complex disease, like cancer, with many contributing factors. The consequences of telomere truncation are only one factor.
Further, murine biology has signficant differences from human biology. Mice are less complex organisms, with rather short lifespans. Mice seem to retain some degree of telomerase activity throughout their lives, so they are not as well adapted to going for long periods without it.
It is noteworthy that evidence was not found that TERT-ER mice treated with 4-OHT became more susceptible to cancer. Still, mice don't live very long, and they are adapted to maintain active telomerase. Humans are different. If telomerase is artificially kept active for years in humans, incipient tumorigenicity could be accelerated.
Lastly, it's not necessarily easy to raise human telomerase activity levels in the first place. Although some telomerase-activating factors are known, they have not been tested extensively in humans for long periods of time, so their safety and efficacy profile is not known.
These research results are quite interesting – but they only indicate the need for much more investigation.
Further reading: (* = especially recommended)
* Telomerase reverses ageing process (11/28/10)
* The Curious Case of the Backwardly Aging Mouse (11/29/10)
* Partial reversal of aging achieved in mice (11/29/10)
Harvard scientists reverse the ageing process in mice – now for humans (11/28/10)
Gene reactivation reverses aging-related brain deficits in mice (11/30/10)
Age-Reversing Drugs on the Horizon? Not So Fast (11/29/10)
Telomere Tweaks Reverse Aging in Mice (11/29/10)
Alzheimers and aging advances uncovered (11/29/10)
An enzyme leads the dance of immortality and death (11/29/10)
Scientists Find Way to Partially Reverse Aging in Mice (11/29/10)
While oxidative stress is certainly a significant factor in aging, possibly the most significant, there are others. One of these is the limitation on a cell's ability to undergo cell division in order to produce new cells of the same type. This is especially important in tissues that regularly need to regenerate, such as skin and intestinal tissue. Everyone now knows about telomeres, whose main function is to constitute protective end caps on chromosomes. The limitation on number of cell divisions happens since about 100 base pairs are lost from telomeres during each cell division. When telomeres eventually become too short signals that are similar to those associated with other kinds of DNA damage shut down a cell's ability to divide further. This mechanism indirectly helps mitigate the risks of DNA damage that are present every time a cell divides – an inherently tricky process.
However, this limitation on cell division isn't acceptable during embryonic development, when an organism's cell count is doubling most rapidly. So evolution has provided an enzyme – telomerase – that can rebuild telomeres, but is most active only during embryonic development. Except, of course, in cells that have become cancerous, where the ability to divide without limit is the name of the game. We discussed telomeres and telomerase in some detail a little over a year ago in this article, so you can go there for more.
Because of the risk of cancer, it seems imprudent to reactivate telomerase for the long term within an organism, especially in long-lived animals such as humans. (In animals like mice, which live fast and die young, it's a different matter. Telomerase may remain somewhat active in mice during adulthood. (Mentioned here.)) But what if it were possible to reactivate telomerase for a relatively short period of time (compared to the whole lifespan)... might that provide an opportunity to rebuild telomeres to some extent? Even better, might that reverse, at least to some extent, the ravages of aging?
We now have some research that seems to provide a fairly unambiguous affirmative answer... in a rather special case: Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.
But didn't we just say that mice may retain telomerase activity throughout their lives? Yes, however it's a relatively simple matter to "knock out" the main telomerase gene in mice (Tert). When that's done the resulting strain of knock-out mice – after several generations – have shortened lifespans and a general phenotype of age-related debilities, as one would expect. (The first few generations apparently still have sufficiently long teleomeres.)
Unfortunately, that's not a good enough model, since without a Tert gene, the organism has no way to manufacture telomerase. Simply giving the knock-out mice repeated infusions of telomerase is not a good way to ensure uniform distribution of the enzyme to all of the organism's cells. What to do? The experimenters came up with a rather clever solution. Normally the way that telomerase is activated in cells is by means of an "estrogen receptor" (ER), to which a form of the hormone estrogen (17β-estradiol to be precise) can bind and enable transcription of Tert. This ER can be tweaked so that estrogen binds to it only in the presence of another chemical, 4-hydroxytamoxifen (4-OHT).
A special form of the Tert gene that includes this special ER can be "knocked-in" to the mouse germline. It then turns out that 4-OHT can be efficaciously supplied to a TERT-ER mouse (in the form of a time-release subcutaneous pellet) to turn telomerase expression on and off at the experimenter's will. With that technology in place, the researchers were then able to perform a series of experiments demonstrating, in these special mice, that a month-long burst of telomerase could actually reverse a number of the ill effects of telomerase deprivation.
The first step was to show that without 4-OHT the TERT-ER mice (after a few generations) had many of the same problems, in the same degree, as later generations of knock-out mice that lacked Tert entirely. The TERT-ER mice (all of which were male) showed no signs of telomerase activity. Tissues in highly proliferative organs such as testes, spleen, and intestines showed notable atrophy. Lifespan of TERT-ER mice was about half that of normal ("wild type") mice.
The first test to investigate the effects of telomerase reactivation by means of 4-OHT was done in vitro. Fibroblast cells from TERT-ER mice were cultured and found to be essentially senescent and not undergoing cell cycles. But when the cells were placed in media containing 4-OHT, teleomerase was reactivated, telomeres lengthened, and cell proliferation resumed.
Some TERT-ER mice were then given a 4-week treatment of 4-OHT (subcutaneous pellets). At the end of that treatment there was a marked reversal of the degeneration that has occurred in testes, spleen, liver, and intestinal tissues, as well as resumption of sperm production. Survival time of these treated mice also increased. At the same time, 4-OHT had no effects on control mice that weren't lacking in telomerase and didn't have tissue degeneration.
Noteworthy results were obtained from tests to assess nervous system condition. Proliferation of neural progenitor cells was found to resume in TERT-ER mice treated with 4-OHT. Normal numbers of mature oligodendrocytes reappeared. Lastly, high-level neurological functions were restored, as indicated by resumption of nearly normal olfactory sensitivity.
An interesting conclusion that can be drawn from the neurological results is that neural progenitor cells probably survive loss of telomeres, so that they can rebuild neural cell populations if telomeres are repaired.
The really interesting question, of course, is the extent to which these results may apply, in some form, to humans. Unfortunately, there are a number of reasons to be skeptical. For one thing, telomere shortening is only one factor, and quite possibly not the main one, in human aging. Aging can be thought of as a complex disease, like cancer, with many contributing factors. The consequences of telomere truncation are only one factor.
Further, murine biology has signficant differences from human biology. Mice are less complex organisms, with rather short lifespans. Mice seem to retain some degree of telomerase activity throughout their lives, so they are not as well adapted to going for long periods without it.
It is noteworthy that evidence was not found that TERT-ER mice treated with 4-OHT became more susceptible to cancer. Still, mice don't live very long, and they are adapted to maintain active telomerase. Humans are different. If telomerase is artificially kept active for years in humans, incipient tumorigenicity could be accelerated.
Lastly, it's not necessarily easy to raise human telomerase activity levels in the first place. Although some telomerase-activating factors are known, they have not been tested extensively in humans for long periods of time, so their safety and efficacy profile is not known.
These research results are quite interesting – but they only indicate the need for much more investigation.
 | Jaskelioff, M., Muller, F., Paik, J., Thomas, E., Jiang, S., Adams, A., Sahin, E., Kost-Alimova, M., Protopopov, A., Cadiñanos, J., Horner, J., Maratos-Flier, E., & DePinho, R. (2010). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice Nature, 469 (7328), 102-106 DOI: 10.1038/nature09603 |
Further reading: (* = especially recommended)
* Telomerase reverses ageing process (11/28/10)
* The Curious Case of the Backwardly Aging Mouse (11/29/10)
* Partial reversal of aging achieved in mice (11/29/10)
Harvard scientists reverse the ageing process in mice – now for humans (11/28/10)
Gene reactivation reverses aging-related brain deficits in mice (11/30/10)
Age-Reversing Drugs on the Horizon? Not So Fast (11/29/10)
Telomere Tweaks Reverse Aging in Mice (11/29/10)
Alzheimers and aging advances uncovered (11/29/10)
An enzyme leads the dance of immortality and death (11/29/10)
Scientists Find Way to Partially Reverse Aging in Mice (11/29/10)