An international research team has identified a key role for a gene that is expressed in muscles and neurons, in the regulation of age-related motor function decline, increasing frailty and even lifespan in aging Caenorhabditis elegans nematode worms. Shawn Xu, PhD, professor of molecular and integrative physiology at the University of Michigan Medical School, and a team at the University of Michigan Life Sciences Institute (LSI) headed the studies, which demonstrated how targeting the slo-1 (slowpoke potassium channel family member 1) gene or its protein SLO-1 held back motor function decline and extended longevity in older C. elegans worms by acting at the neuromuscular junctions (NMJs) of motor neurons.
SLO-1 is the nematode ortholog of the mammalian potassium channel known as the BK channel, and the researchers say their findings in the C. elegans model could open up new avenues of research into aging in higher organisms. “Studying aging in organisms with longer lifespans is a major investment,” said Xu. “But now we have identified a molecular target, a potential site, and specific timing, which should facilitate further investigation.” Reporting their findings in Science Advances, the researchers concluded, “Our results would encourage researchers to examine the role of BK channels in aging in mammals.” Their paper is titled, “Genetic and pharmacological interventions in the aging motor nervous system slow motor aging and extend lifespan in C. elegans.”
Aging is associated with a progressive decline in the function of many different organs and tissues. Organisms ranging from worms to humans all demonstrate age-related weakening in motor function, for example, the authors write. This is one of the most “prominent features of normal aging.” While C. elegans nematode worms begin to lose motor activity in early adult life, humans will typically start to experience some motor decline in mid life. “This aging process ultimately leads to frailty, resulting in falling that causes injury and mortality … motor deficits represent one of the main risk factors for falling in elderly humans,” the authors noted. And while the ability to delay or slow motor aging would have obvious benefits, “this, however, has remained a challenge.”
C. elegans is an established genetic model organism for studying aging, and prior research has characterized age-dependent motor decline in the organism. “We previously observed that as worms age, they gradually lose physiological functions,” commented Xu. “Sometime around the middle of their adulthood, their motor function begins to decline. But what causes that decline?”
Aging in roundworms is associated with the progressive decline in synaptic release from motor neurons at NMJs and this contributes to the problems with motor activity that typically accompany aging. “Synaptic release from motor neurons at NMJs is known to undergo a progressive functional decline beginning in early life, which contributes to age-dependent motor activity decline in C. elegans,” the authors wrote.
Xu’s team set out to identify a molecular target that they could manipulate either pharmacologically or genetically to slow motor aging and potentially even increase lifespan. “… we considered the genes that function to dampen synaptic release from motor neurons at NMJs,” the researchers noted. They focused their studies on SLO-1, which has previously been shown to repress synaptic transmission at neuromuscular junctions. The team’s comparative studies in slo-1-knockout and wild-type C. elegans worms showed that motor activity declined more slowly with age in the slo-1 mutant worms, which were able to maintain a higher motor activity in mid-late life, and which “strikingly,” also lived longer than wild-type worms, the authors wrote. “These results demonstrate that loss of SLO-1 not only slows motor aging, but also promotes longevity.”
Interestingly, the team found that genetically deleting slo-1 had beneficial effects on motor aging and lifespan when knockdown was effected in aged, but not in young worms. Similarly, pharmacological blockade of SLO-1 using the BK channel blocker paxilline effectively slowed motor aging and extended lifespan in aged, but not young C. elegans nematodes. “Thus, similar to the case with genetic knockdown, pharmacological inhibition of SLO-1 in aged, but not young, worms can also promote longevity and slow motor aging,” the team stated.
Tests indicated that SLO-1 acts in motor neurons to regulate longevity and motor aging in the worms in mid-late life. Genetically or pharmacologically ablating SLO-1 effectively acted to slow aging of motor neurons at NMJs by removing the SLO-1-related dampening of synaptic release from NMJs. “These results demonstrate that pharmacological blockade of SLO-1 can promote synaptic release from motor neurons at NMJs in aged worms, suggesting a potential mechanism underlying paxilline-induced beneficial effects on aging,” the authors commented. “It’s not necessarily ideal to have a longer lifespan without improvements in health or strength,” added Xu. “But we found that the interventions improved both parameters—these worms are healthier and they live longer.
The team pointed out that the differential effects of targeting SLO-1 in younger and older worms indicate that SLO-1 and possibly NMJs may have complex roles in motor aging and longevity, “underscoring that timing is an important factor for consideration when designing strategies to modulate aging,” they wrote. “Further work is needed to delineate the detailed mechanisms underlying the differential roles of SLO-1 in aging in early versus mid-late life.” The combined results indicated that SLO-1 may have an important role in motor function in early life. “In this case, blunting its activity in early life would not be beneficial for motor functions or lifespan.” Even so, the authors stated, “Our results demonstrate that genetic and pharmacological interventions in the aging motor nervous system can promote both healthspan and lifespan.”
BK channels are evolutionarily conserved, and are involved in dampening neuronal excitability and synaptic transmission, they continue. BK channel overactivation has also been linked with dampened synaptic transmission during the early stage of Alzheimer’s disease in a mouse model, and has been suggested to contribute to progression of the disorder. “Notably, such a symptom can be mitigated by BK channel blockers such as paxilline.” Interestingly, BK channel knockout mice display some motor function changes at a young age, similar to slo-1 mutant worms. “The fact that BK channels play a modulatory rather than essential role in neuronal excitability and synaptic transmission offers an advantage for targeting these channels for potential therapeutic interventions,” the team concluded.
