TET2 Overexpression Enhances Neurogenesis and Cognitive Function in Old Mice

Heterochronic parabiosis is the process of linking the circulatory systems of an old and young animal. It improves measures of aging in the older individual, and worsens measures of aging in the younger individual. Researchers use this technique to try to pinpoint the important signaling and other cell behavior changes that take place with advancing age. This isn't just a matter of looking at signals in the bloodstream, however. Researchers can analyze any of the changing gene expression patterns and biochemical relationships inside cells, as they respond to the altered environment. That is the case in the open access paper I'll point out here; a research team experimenting with heterochronic parabiosis found that it increased expression of TET2 in old mice, and they present evidence to implicate reduced levels of TET2 in age-related cognitive decline.

Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain

During aging, the number of neural stem/progenitor cells (NPCs), and subsequently neurogenesis, precipitously declines in the subgranular zone of the dentate gyrus (DG) in the hippocampus. Mounting evidence in animal models indicates the potential for rejuvenation of regenerative and cognitive functions in the aging brain through interventions, such as heterochronic parabiosis (which exposes aged animals to young blood). However, the ability to utilize this neurogenic potential is predicated on identifying molecular targets that reverse the effects of aging in the brain.

Recent studies have begun to link changes in the functions of epigenetic mediators to age-related regenerative decline. Interestingly ten eleven translocation methylcytosine dioxygenase 2 (Tet2) is emerging as a potential epigenetic regulator of aging. Human genetic studies identified an increased frequency of somatic TET2 mutations with age that are associated with elevated risk for aging-associated disorders, such as cancer, cardiovascular disease, and stroke. Notwithstanding, the involvement of Tet2 in mediating the aging process in the adult brain has yet to be investigated.

Here we demonstrate that Tet2 offsets age-related neurogenic decline and enhances cognition in the hippocampus of adult mice. We detect an age-dependent decrease in the levels of Tet2 in the aging hippocampus coincident with decreased adult neurogenesis. Mimicking an age-related loss of Tet2 in the adult neurogenic niche of the hippocampus, or adult NPCs, impairs regenerative capacity and associated hippocampal-dependent learning and memory processes. Conversely, increasing Tet2 in the hippocampus of mature animals increases restores adult neurogenesis to youthful levels and enhances cognitive function.

Recently, it has been demonstrated that constitutive whole-body loss of Tet2 yields opposing effects on neurogenic processes, resulting in increased adult NPC proliferation but decreased neuronal differentiation. In contrast, our data indicate that decreasing Tet2 expression acutely in the adult neurogenic niche impairs all stages of hippocampal neurogenesis, while loss of Tet2 in adult NPCs impairs neuronal differentiation processes. These data point to differential regulation of distinct stages of neurogenesis by Tet2 that arise from the loss of Tet2 at the level of the whole organism, neurogenic niche, and adult NSC during development versus adult ages. In the context of aging, our data implicate decreased Tet2 in the aging hippocampus with age-related regenerative decline.

Aging is a process of layers. At the bottom of it, the root causes are forms of molecular damage: an accumulation of broken, misbehaving cells; growing deposits of metabolic waste; mutated mitochondrial DNA; and so on. Above this is a very complicated and poorly mapped middle layer in which cells react to damage, changing countless signals and behaviors in response. Some of this is compensation, with varying degrees of success, and some of it wild flailing that makes everything worse. Then at the upper layer we find the familiar age-related diseases and classes of organ dysfunction, the sort of thing that is described in terms of the capacity that is failing or lost rather than how that failure or loss happened: kidney failure; dementia; heart disease; and so on.

Most research into aging starts at the top layer, with the evident symptoms of age-related disease, and then works just a little way back down into the upper part of the middle layer, trying to make sense of the final part of the chain of cause and effect. Then the researchers usually try to build therapies rather than carry on deeper. The work here is an excellent example of the way in which this proceeds. Having identified reduced levels of TET2 as a proximate cause of loss of neurogenesis and cognitive function, the next step is not to ask why levels of TET2 are lower, but to try to override that change. When this strategy is repeated over and again across the research community, is it any wonder that we have very little detailed knowledge of how the known root causes of aging - those summarized in the SENS rejuvenation research portfolio - interact and progress to give rise to all the various measures of aging.

Not that I think it is necessarily the right thing to do to work further downwards through the middle layer to the bottom. Quite the opposite, in fact. I think the most economical way forward is to build repair therapies capable of addressing the damage that causes aging, changing the bottom layer, and then see what happens next as those repairs propagate their effects. In the case of senescent cells and aging, this approach is ongoing, and generating new knowledge at a much, much faster pace than was the case in the years prior to the emergence of the first senolytic therapies capable of selectively destroying these cells. In a better world, the research community would have enough funding to energetically pursue all options: compensatory treatments as well as those that address root causes. As it is, it is largely the former that take place, while the latter remain neglected. Given that repairing the root causes should be far more effective than compensating for a small slice of their downstream effects, this is a real problem.


seems like you try to link everything with sens ... like they are holding the aging solution and everybody else is plain wrong ... which is not surprising as you (like sene) are stuck to the same old approach.

beside other things, this study spells clearly that there are pro-youthful "factors" that leads to rejuvenation, and not the idea that you/sens were trying to force into community that the rejuvenation from parabiosis is about "filtering out the damage". and you keep repeating the same thing without looking at the results from real studies.

so you better start reading the studies as they are, rather than try to put words into their mouth, in order to prop sens ideas. this is real science not professional blogging that you do 24/7.

if you still do not comprehend the study, read it again:

"Overexpressing Tet2 in the hippocampal neurogenic niche of mature adults increased 5hmC associated with neurogenic processes, offset the precipitous age-related decline in neurogenesis, and enhanced learning and memory. Our data identify Tet2 as a key molecular mediator of neurogenic rejuvenation."

and as a summary for you:

- Tet2 and 5hmC Levels Decrease in the Aged Hippocampus and Are Associated with Neurogenic Processes
- Reducing Tet2 in the Young Adult Hippocampus Impairs Neurogenesis
- Reducing Tet2 in the Young Adult Hippocampus Impairs Cognitive Function
- Decreased Tet2 in the Aged Hippocampus Is Reversed in a Heterochronic Parabiosis Model of Brain Rejuvenation
- Restoring Tet2 in the Mature Adult Hippocampus Rescues Age-Related Regenerative Decline
- Restoring Tet2 in the Mature Adult Hippocampus Enhances Cognitive Function"

would be great if you would focus on what you and sens understand, rather than rambling around and post lots of non-sens-e things.

Posted by: abc at February 25th, 2018 7:45 AM

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