Reversal of Age-Associated Tissue Degeneration in Mice
Research into slowing the aging process has had some success over the past twenty years. For example, genetic alterations of the pathways involving telomerase activity, the mammalian target of rapamycin, and insulin-signalling have increased the life spans of rodents. Caloric restriction slows aging, increases the life spans of many different species, and often slows and attenuates age-associated disease development, including type II diabetes, neurodegeneration, atherosclerosis, and cancer1. While aging has been slowed by such methods, there are few examples of age-associated tissue, organ, or whole-animal degeneration being reversed by any manipulation, particularly in mammals.
Aging research has focused extensively on the role of telomeres in aging. Telomeres are DNA structures found at the end of chromosomes which protect chromosomal ends from inappropriate and often deleterious chromosomal rearrangements. In most cell types telomeres shorten at each cell division and eventually this shortening leads to cellular and organismal aging, and an inability of the cell to divide further (called replicative senescence or the “Hayflick Limit” The enzyme telomerase lengthens telomeres and while it’s expressed in some cell types, its expression levels are usually too low to stop telomere shortening2. Interestingly, compared to humans mice have unusually long telomeres and mice lacking telomerase activity are viable up to six generations. At generations three to four and beyond, telomerase-deficient mice show increasing premature aging, with short life spans, organs showing premature aging, and cells that grow poorly in culture and show unstable chromosomes3.
In a recent paper Jaskelioff et al. (4) demonstrated reversal of aging-associated tissue and whole-organ degeneration by manipulating telomerase activity in mice. Mice completely lacking normal telomerase activity, but carrying a telomerase whose expression could be induced by exposure to the drug 4-hydroxytamoxifin (4-OHT) were genetically engineered and bred to generation four (G4, see Figures). At generation four the mice showed short telomeres and numerous features associated with telomere shortening, including increased abnormal chromosomal fusions, poor cell growth in culture, and tissue atrophy, especially in organs with high cell proliferation, such as the tests, spleen, and intestinal lining. Not surprisingly, many organs in these mice, such as the testes, spleen, and brain were smaller than those of the same mice at generation one. Last, the mice had significantly lower fertility, and their life spans averaged 43.5 weeks compared to 86.8 weeks for mice with normal telomerase function.
Treatment of the generation four telomerase lacking mice and their cells in culture, with 4-OHT for four weeks to induce the telomerase enzyme had profound effects. Cells taken from these mice re-gained their ability to grow and divide in culture (Figure 1). Thus re-activation of telomerase allowed “old cells” incapable of dividing, to begin dividing again.
After four weeks of 4-OHT treatment the mice showed changes in several organ systems. The testes of treated with 4-OHT showed increased seminiferous tubule size compared G4 mice not treated with 4-OHT (Figure 2).
Within the central nervous system neurons showed a thicker diameter and thicker myelination in the olfactory areas of the brain (Figure 3).
Mice that were treated with 4-OHT also had increased olfactory function. Thus re-activation of telomerase in G4 mice increased the mouse’s sense of smell and conferred a younger neuronal cell shape. Last, treatment with 4-OHT increased the overall size of the brains in treated mice (Figure 4).
Thus telomerase activation increased brain size without causing any obvious brain abnormalities. Since the brain is not an organ that usually has a high number of dividing cells (low proliferative index), this finding is very interesting. It appears possible to rejuvenate an old brain and partially reverse aging-induced brain atrophy. The authors would like to point out that prior to the publication of this paper, the reversal of aging-induced brain atrophy was considered either unlikely or impossible.
The study by Jaskelioff et al. (4) is a rare example of aged-damaged tissue and organs actually undergoing partial rejuvenation. This was seen in organs with a high rate of cell division, as well as in the brain where cell division is very low. Until recently essentially all efforts to alter aging have focused (with some success), and slowing the aging process. This is one of the first studies ever done showing reversal of the aging process to a younger phenotype and genotype (as measured by telomere length).
Two caveats should be mentioned. First telomere activation might increase cancer in these mice. Although no increase in cancer was detected in this study, it went on for only four weeks. It’s possible that the cancer rates in these mice might be increase at later times with longer 4-OHT treatment4. Additionally, telomeres are very long in mice compared to humans and it’s presently not known how precisely the data presented here could relate to human aging3,4. However, this work is a landmark in the analysis of aging and indicates that it might be possible not only to slow aging, but reverse it, at least for short periods. More work will be needed to analyze the long-term effect of telomerase re-activation in aged tissue.
- Protein Cell. 2014;5:21-35.
- Telomeres, Telomerase and Aging. H+ March 28, 2011
- Cell. 1997;91:25-34.
- Nature. 2011;469:102-6.