The aging process is a fascinating yet complex journey for our bodies, and one area that has long intrigued scientists is its impact on our cognitive abilities. But here's the twist: it's not just about diseases like Alzheimer's or Parkinson's.
Michael Lodato, a geneticist from the University of Massachusetts (UMass), has a unique perspective on this. He believes that somatic mutations, which occur throughout our lives, play a pivotal role in how our brains age. In a groundbreaking study published in Nature, Lodato and his team delved into the genetic and genomic dynamics of the human brain across different life stages, from infancy to old age.
Their findings? Neurons do accumulate mutations as we age, but these mutations target short housekeeping genes responsible for basic cell maintenance, rather than longer genes that drive neuron-specific functions.
Most research on brain aging has focused on classical age-related diseases, but there's another aspect to this story - what researchers call "healthy aging." Even without these diseases, our executive brain functions decline over time. Lodato and his team believe this decline is due to accumulated somatic mutations from DNA damage and repair events.
"Since neurons don't replicate, these mutations can have long-term consequences," Lodato explains.
To understand how neurons age without disease, Lodato turned to single-cell whole genome (scWGS) and single-nucleotide RNA sequencing (snRNA-seq) techniques. These allowed him to detect neuronal mutations with single-cell resolution, as neurons are post-mitotic and don't divide.
Lodato and his team, including co-lead author Ailsa Jeffries, examined brain cells from 19 neurotypical donors ranging from infants to centenarians. They collaborated with computational biologist Zhiping Weng from UMass to analyze the data, focusing on isolating aging-related effects from natural variability.
"We basically tried every which way to defeat our hypotheses," Weng recalled. To ensure the robustness of their findings, they compared their data to three other large datasets collected by other researchers.
Their analysis revealed some intriguing insights. They identified 2,803 genes that were differentially expressed with age, with more genes being downregulated than upregulated. Housekeeping genes, typically linked to cell survival, metabolism, and ribosomal translation, were downregulated in aging neurons, while neuron-specific gene expression remained unchanged.
Additionally, they found no age-related changes in the ratio of excitatory to inhibitory neurons or neurons to glia. There was also no loss of neuronal subtypes or expansion of reactive microglia that could indicate immune activation.
"When I got into this field, I thought there were fewer neurons in the aging brain, but that doesn't seem to be the case," Lodato remarked. "The neurons are still there, doing their job, but their metabolism and homeostasis seem dysregulated. They're becoming less active."
Their scWGS analysis further showed that somatic mutations accumulate at a rate of 15.1 per neuron per year. While these mutations occur randomly, specific patterns and signatures can be identified. Lodato's team found two distinct signatures that accounted for aging-related somatic mutation accumulation in neurons.
The first, dubbed A1, was described as a "molecular clock of aging" due to its increasing visibility over time. It accounted for 12.1 of the 15.1 mutations per year. The other signature, A2, was related to mutations in DNA repair genes, which Lodato believes might be brain- or neuron-specific.
An interesting observation was that aging neurons downregulated shorter genes but maintained or increased expression of longer genes. This could be because shorter genes, like housekeeping genes, need to be accessed more often, leading to increased transcription frequency and more opportunities for somatic mutations. Jeffries noted that longer genes are linked to unique protective mechanisms.
"Topoisomerases aid in the expression of long genes by unwinding them [for transcription], and neurons express more topoisomerases than non-neuron cells," she explained. "This activity could be protective."
Lauren Donovan, a neuroscientist at Stanford University not associated with the study, praised the comprehensiveness and robustness of the study. She suggested that future studies could delve deeper into the patterns observed, offering a platform to identify genes more susceptible to somatic mutations.
Lodato and Weng's work is just the beginning. Their lab is leading the Data Analysis and Coordination Center component of the National Institutes of Health-funded Multi-omics for Disease and Health Consortium (MOHD).
"If we can clearly identify changes to the genome and transcriptome, maybe the epigenome or proteome [too], we can tightly tie a mutation to a functional consequence," Lodato said. Weng added, "We're sharpening our analysis weapons, ready for new data for this project."
So, what do you think? Do these findings challenge your understanding of healthy aging? Feel free to share your thoughts and questions in the comments below!
