Unlocking the Secrets of Aging Brains

Researchers have identified the mechanisms that explain why some long-lived mutants of the model organism Caenorhabditis elegans experience cognitive decline, while others retain their learning and memory abilities into old age. 

The study, initially published as a Reviewed Preprint in eLife and now available in a revised version, offers strong proof of the processes by which C. elegans worms carrying a mutation in the daf-2 gene outlive their normal counterparts in terms of cognitive function.

The results may help develop methods for preventing the cognitive deterioration that comes with aging in people.

As our society ages, cognitive decline is becoming an increasingly significant public health concern, with global cases of dementia expected to triple by 2050 according to research presented at the 2021 Alzheimer’s Association International Conference. Understanding and preventing the underlying issues of neuronal structure and behavioral decline associated with ageing is therefore crucial for societal health.”

Yifei Weng, Study Lead Author and Doctoral Candidate, Department of Molecular Biology, Princeton University

Being a model organism with a simple nervous system and a short lifespan, C. elegans is frequently used in biology research, especially when examining the effects of aging. Research conducted on C. elegans may be relevant to humans because it harbors many of the genes involved in neuronal function found in mammals.

The Insulin/IGF-1-like signaling (IIS)/FOXO pathway is a regulatory system that controls growth, metabolism, and lifespan and is highly conserved across species.

A crucial component of this pathway is the daf-2 Insulin/IGF-1 receptor; worms carrying a genetic mutation in this receptor, known as daf-2 worms, exhibit improved memory in their early adulthood and a notable increase in learning and memory span with age, though the mechanisms underlying the latter are still unknown. Weng and associates, therefore, set out to determine how aging daf-2 worms prevent cognitive decline as they age.

Initially, the scientists looked into the variations in gene expression commonly seen in C. elegans neurons. They analyzed neurons taken from adult worms between days one and eight of adulthood, when the worms had already lost their ability to learn and remember things, using a sequencing method known as RNA-seq.

Genes linked to neuronal function showed decreased activity in the aged worms, while genes involved in protein synthesis, breakdown, and regulation showed increased activity.

The team reduced the expression of three genes whose activity is higher in aged animals and conducted behavioral assays to determine whether the specific increased expression of these genes with age was beneficial or detrimental.

Lowering the expression of each of the three genes enhanced the worms' ability to remember things. This suggests that lowering the expression of some neuronal genes that become more abundant with age may benefit the animal and positively affect memory and learning.

It has previously been demonstrated that the DAF-16/FOXO transcription factor is necessary for the enhanced cognitive capacity of daf-2 worms. Therefore, the researchers compared the genetic profile of neurons isolated from eight-day-old daf-2 worms to those isolated from worms of the same age but with a mutation that caused the DAF-16 transcription factor to lose its function (daf-16;daf-2 worms).

In comparison to the daf-16 and daf-2 worms, the scientists found 570 upregulated and 814 downregulated genes in the daf-2 neurons. Numerous upregulated genes were associated with stress responses, such as heat stress, oxidative stress, metal stress, and proteolysis, a process in which genes aid in the breakdown of proteins and are crucial for preserving the health and function of cells.

The researchers examined the impact of the eight most likely culpable genes on cognitive function in C. elegans by reducing their expression. Three of the eight genes examined had reductions that considerably affected the worms' capacity for learning. Those genes and the loss of two more genes, C44B7.5 and alh-2, greatly diminished the worms' short-term memory capacity.

What’s possibly even more intriguing is that the daf-2-regulated genes in aged neurons are new targets of the IIS/FOXO pathway because they differ from those in young neurons. The researchers discovered that 36 of the top 100 upregulated genes have mammalian counterparts. It has been discovered that 32 (89%) of these 36 genes with conserved proteins in mammals have roles in enhancing neuronal health.

These homologs in mammals guard neurons from toxic metabolites and protein aggregation, preserve synaptic organization and neuronal homeostasis, aid in healing neuronal damage, and preserve regular neuronal function. Together, these genes may have neuroprotective properties that shield neurons from environmental damage as they age. This could be a novel way for daf-2 worms to preserve their neurons.

Our data suggest that genes that are differentially regulated in eight-day-old daf-2 mutants may aid in slowing neuronal function decline and behavioral changes associated with ageing. Furthermore, memory maintenance with age might require additional genes that function in promoting stress resistance and neuronal resilience.”

Coleen Murphy, Study Senior Author and Director, Lewis-Sigler Institute of Integrative Genomics

Coleen Murphy is also the Professor of Molecular Biology at Princeton University.

Weng said, “This study provides a greater understanding of the mechanisms underlying neuronal ageing, and could provide useful insights to aid the development of ageing interventions.”