Lifespan of neurons is uncoupled from organismal lifespan

Abstract

Neurons in mammals do not undergo replicative aging, and, in absence of pathologic conditions, their lifespan is limited only by the maximum lifespan of the organism. Whether neuronal lifespan is determined by the strain-specific lifetime or can be extended beyond this limit is unknown. Here, we transplanted embryonic mouse cerebellar precursors into the developing brain of the longer-living Wistar rats. The donor cells integrated into the rat cerebellum developing into mature neurons while retaining mouse-specific morphometric traits. In their new environment, the grafted mouse neurons did not die at or before the maximum lifespan of their strain of origin but survived as long as 36 mo, doubling the average lifespan of the donor mice. Thus, the lifespan of neurons is not limited by the maximum lifespan of the donor organism, but continues when transplanted in a longerliving host.Purkinje cells | dendrites M edian and maximum lifespan are characteristic of a species. However, whether cellular aging is the major determinant of organismal aging is still debated (1, 2). Replicative aging of continuously dividing cells is well characterized in vitro and in vivo (3). On the contrary, aging of terminally differentiated cells is less characterized and often equated with chronological aging (3). The latter is thought to include all age-related changes in a cell as a result of the stochastic accumulation of structural damage and their functional consequences. Most postmitotic neurons in the mammalian CNS survive aging (4), but specific differences in the lifespan of distinct neuronal populations have been described. Purkinje cells (PCs), the only output neuron of the cerebellar cortex, even in the absence of pathologic conditions, are progressively lost with aging in humans and mice (5, 6).It is not known if a maximum lifespan exists for any postmitotic cells of mammals, including neurons. To address this issue, we exploited the differences in maximum lifespan of different strains of mice and rats. Although the two species have similar aging rates, and, in captivity, under optimal conditions, maximum lifespan of single outbreed individuals may reach 4 y (7), diverse strains of mice and rats differ significantly in their maximum lifespan, and these differences are genetically transmissible (8, 9). In utero, into the developing CNS of embryonic day (E) 15 embryos of Wistar rats, we transplanted cerebellar neuroglial precursors obtained from E12 mice embryos of mixed B6;129Sv background expressing EGFP in all cells (10). After birth of the transplanted rat embryos, we studied if the engrafted mouse cells survived for the entire life of the rat host. ResultsAn outline of the experiment is presented in Fig. 1.Recipient Rats Survived as Long as Two Times the Average Survival of Donor Mice. With the exception of animals electively perfused within 18 mo of life, the remaining graft recipient rats (n = 59; 86%) were let survive until moribund and unlikely to outlive longer than 48 h. Maximum survival of live-born recipient rats w...

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“…Postmitotic cells such as neurons can survive and function normally for the entire life of the animal, in some cases (e.g., fish, tortoises, whales) for over 200 years. Interestingly, the cellular niche can control the lifespan of these neurons; for example, embryonic neuron precursors from short-lived mice (~18 month life span) that are transplanted into rats (~30 month life span) live twice as long (Magrassi et al, 2013). The neurons arising from the transplanted neuronal precursors(Purkinje cells) remain smaller than the corresponding rat neurons but retain normal polarity and orientation with age; they also show a similar age-dependent loss of dendritic spines with age as seen in the rat neurons.…”

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