Molecular changes associated with spinal cord aging

Abstract

Age-related muscle weakness and loss of muscle mass (sarcopenia) is a universal problem in the elderly. Our previous studies indicate that alpha motor neurons (α-MNs) play a critical role in this process. The goal of the current study is to uncover changes in the aging spinal cord that contribute to loss of innervation and the downstream degenerative processes that occur in skeletal muscle. The number of α-MNs is decreased in the spinal cord of wildtype mice during aging, beginning in middle age and reaching a 41% loss by 27 months of age. There is evidence for age-related loss of myelin and mild inflammation, including astrocyte and microglia activation and an increase in levels of sICAM-1. We identified changes in metabolites consistent with compromised neuronal viability, such as reduced levels of N-acetyl-aspartate. Cleaved caspase-3 is more abundant in spinal cord from old mice, suggesting that apoptosis contributes to neuronal loss. RNA-seq analysis revealed changes in the expression of a number of genes in spinal cord from old mice, in particular genes encoding extracellular matrix components (ECM) and a 172-fold increase in MMP-12 expression. Furthermore, blood-spinal cord barrier (BSCB) permeability is increased in old mice, which may contribute to alterations in spinal cord homeostasis and exacerbate neuronal distress. Together, these data show for the first time that the spinal cord undergoes significant changes during aging, including progressive α-MNs loss that is associated with low-grade inflammation, apoptosis, changes in ECM, myelination, and vascular permeability.

Neuron‐specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice

“…A significant age‐related loss of motor neurons was also evident by 18 to 22 months in control mice. Consistent with these data, we previously measured motor neuron counts in young (3‐ to 6‐month‐old) versus old wild‐type (24 to 27 month) C57Bl6 J mice and reported a similar (41%) decline in motor neuron number with age (Piekarz et al, 2020). These findings support a role for oxidative stress‐induced neuron loss in the spinal cord of the young i ‐mn‐Sod1KO mice that is exacerbated as a function of age.…”

“…Motor neuron count and area in lumbar region of spinal cord were determined as described previously (Piekarz et al, 2020). Sections were stained with NeuN antibody (Cell Signaling Technology) followed by Alexa Fluor ® 488 F(ab)2 Fragment of Goat Anti‐Rabbit IgG (H + L) antibody.…”

“…Motor neuron count and area in lumbar region of spinal cord were determined as described previously (Piekarz et al, 2020). Sections…”

Blood-Spinal Cord Barrier: Its Role in Spinal Disorders and Emerging Therapeutic Strategies

“…A recent finding by Piekarz et al [211] shows significant loss (up to 41%) of alpha motor neurons (α-MNs) with increasing age in mice. In addition, loss of myelin, compromised neuronal viability, increases in the age-related inflammation marker soluble ICAM-1 and the apoptotic marker caspase-3 are all indicative of the degenerative impact of aging on the spinal cord.…”

Deletion of Sod1 in motor neurons exacerbates age-related changes in axons and NMJs associated with premature muscle atrophy in aging mice

“…The reduction in muscle mass and function with age is due to a decrease in the number of muscle fibers and atrophy and weakening of those remaining (Lexell et al, 1986; Brooks and Faulkner, 1988; Lexell et al, 1988). The loss of muscle that occurs with aging occurs in parallel with loss of motor units in both humans and rodents (Campbell et al, 1973; Sheth et al, 2018) and is associated with a 25–50% reduction in the number of motor neurons (Tomlinson and Irving, 1977; Rowan et al, 2012; Piekarz et al, 2020). This appears to be due to selective loss of large fast α-motor neurons leading to an apparent increase in the proportion of type I (slow twitch) or type IIa muscle fibers that is particularly apparent in humans (Narici and Maffulli, 2010; Sonjak et al, 2019).…”