Reprogramming cells in a living animal, transforming them into induced pluripotent stem cells, has the sound of a bad idea – leading to cancer, damage to structures and tissues, inappropriate signaling, and more. One of the interesting discoveries of recent years is that in vivo reprogramming can be quite beneficial, provided that small enough numbers of cells are transformed, or provided that reprogramming is only partial, halted before it progresses far enough to change cell type. It is possible that modest levels of in vivo reprogramming act much like the effects of a stem cell therapy, producing changes in the signaling environment and cell behavior that improve tissue function. Equally, the effects may be more a case of large numbers of cells undergoing some degree of reprogramming, enough to reverse age-related mitochondrial dysfunction and epigenetic change.
The study here demonstrates that excessive in vivo reprogramming is indeed a bad idea, while also showing that old mice have their cognitive function improved by lesser degrees of reprogramming. This is achieved by using mice engineered to express the Yamanaka factors that reprogram cells, but only conditionally, when exposed to an antibiotic. Mice given the antibiotic continually largely die after a few weeks, the inevitable result of too much disruption, too many vital cells being transformed, in one organ or another. Mice given the antibiotic intermittently instead exhibit improved cognitive function, and suffered no increase in mortality over the course of a four month study.
As organisms age, some epigenetic markers are modified. It has been proposed that the removal of these aging-dependent epigenetic modifications may reverse some features of aging. Temporal expression of Oct4, Sox2, Klf4, and c-Myc (also known as the Yamanaka factors, YFs), used for pluripotency cell reprogramming, can cause this removal of epigenetic marks and subsequent reversal of aging features. Indeed, this approach has been successfully used to improve age-associated hallmarks in peripheral tissues of mice. However, little attention has been given to the therapeutic use of YFs in the central nervous system. Importantly, YF expression must be tightly regulated, since it can lead to aberrant mitogenic stimulation or apoptosis.
In this study, we addressed age-dependent changes in brain structures susceptible to premature degeneration. It has been postulated that age-related brain decline mirrors developmental maturation and, accordingly, brain structures with a late development may be the first to degenerate. This notion was first described as Ribot’s law. The dentate gyrus (DG) exemplifies a brain structure that matures after birth and whose functions decline early with age. For example, the DG of 10-month-old mice shows a clear decrease in adult neurogenesis, the process through which functional neurons are generated from adult neural precursors and integrated into existing circuits. In the adult mouse brain, adult neurogenesis occurs at the interface between the DG and hilus, in a region known as the subgranular zone. This type of neurogenesis is involved in learning and memory.
Here, we examined several markers for adult neurogenesis in mice. We found impaired adult hippocampal neurogenesis as the animals aged, thereby supporting previous observations. Our aim here has been to rejuvenate old hippocampal neurons by expressing YFs. However, an extended expression of YFs (continuous protocol) can cause aberrant transcription and cell death. Indeed, around 50% of YF-expressing mice died after 10 days of this protocol. We then tested cyclic induction of YFs. In this protocol, mouse death was prevented. Our results indicate that in mature mice, the expression of YFs results in a partial prevention of those aging-associated changes found in the newborn neurons of adult mice. In addition, YFs show an effect on DG mature neurons that could increase synaptic plasticity in old mice. This increase could explain why mice expressing YFs outperformed same-age wild-type counterparts in a memory test.