Decoding the relationship between ageing and amyotrophic lateral sclerosis: a cellular perspective

Abstract

With an ageing population comes an inevitable increase in the prevalence of age-associated neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), a relentlessly progressive and universally fatal disease characterized by the degeneration of upper and lower motor neurons within the brain and spinal cord. Indeed, the physiological process of ageing causes a variety of molecular and cellular phenotypes. With dysfunction at the neuromuscular junction implicated as a key pathological mechanism in ALS, and each lower motor unit cell type vulnerable to its own set of age-related phenotypes, the effects of ageing might in fact prove a prerequisite to ALS, rendering the cells susceptible to disease-specific mechanisms. Moreover, we discuss evidence for overlap between age and ALS-associated hallmarks, potentially implicating cell type-specific ageing as a key contributor to this multifactorial and complex disease. With a dearth of disease-modifying therapy currently available for ALS patients and a substantial failure in bench to bedside translation of other potential therapies, the unification of research in ageing and ALS requires high fidelity models to better recapitulate age-related human disease and will ultimately yield more reliable candidate therapeutics for patients, with the aim of enhancing healthspan and life expectancy.

The microglial component of amyotrophic lateral sclerosis

“…Ageing is a strong risk factor for ALS ( Pandya and Patani, 2019 ). Emerging evidence has suggested that the microglial transcriptome undergoes vast changes during normal ageing.…”

Neurovascular Inflammaging in Health and Disease

“…While a number of factors have been proposed to contribute to disease progression, family history, male sex and aging are considered to be the major risk factors of ALS [110,111]. Aging in ALS is not only of epidemiological, but also of cellular importance, as neurons are post-mitotic cells and the vulnerability of motoneurons is known to increase in an age-related manner [112]. Despite the primary involvement of motor neurons, astrocytes [113], microglia [114], and infiltrating immune cells [115] have also been implicated in the underlying pathomechanism of the disease.…”

A Non-Toxic Concentration of Telomerase Inhibitor BIBR1532 Fails to Reduce TERT Expression in a Feeder-Free Induced Pluripotent Stem Cell Model of Human Motor Neurogenesis

“…This is a rapidly progressive degenerative disease of motor neurons (MNs) where patients lose the ability to eat, speak, locomote, and breathe, ultimately causing death within 2–5 years of diagnosis. Normal ageing is the largest risk factor for ALS, yet the interplay between ageing and ALS at molecular [ 1 , 2 ] and cellular levels [ 3 , 4 , 5 ] remains incompletely resolved in human MNs. With a dearth of disease modifying therapies available, high fidelity modelling is essential to ensure optimal bench-to-bedside translation and therapeutic discovery for ultimate patient benefit.…”