By Luiza Skowronski Flynn
What if growing older doesn’t mean growing slower? While aging is not “curable”, scientists are looking for ways to slow its process so that with time, our minds remain sharp. A recent study published in June 2023 by the Nutritional Sciences & Toxicology Department at the University of California, Berkeley examined how protein folding in the mitochondria (a subunit of human cells responsible for producing cellular energy) affects neuronal (brain cell) aging.
Mitochondria in the brain require proteins for proper function to ensure the pH of the cell is maintained. When these proteins function in an atypical manner, mitochondrial function declines and cells in the brain fail to properly regenerate. Through this lense, scientists have found that by targeting specific enzymes in DNA, protein folding within the mitochondria may be halted, reducing the destruction of cerebral nervous tissue that would otherwise lead to cognitive decline.
This study focuses on the hippocampal region in the brain, and more specifically, the dentate gyrus, which is responsible for learning and the formation of memory. Within the dentate gyrus, there is a subcategorization of cells called neural stem cells (NSC) that are self-renewing and can become any other type of cell within the central nervous system (CNS). A process called neurogenesis refers to the vital growth and development of NSC within nervous tissue, and the reproduction of these cells has the power to create a healthy memory. The method these researchers used to quantify cognitive ability measures neurogenesis through a process called single-cell RNA sequencing (scRNA-seq), which allows individual cells to be observed by looking at their mRNA.
Scientists are interested in isolating NSC because of its capacity to reveal our brain’s biological age. In an aged brain (or a brain with dementia), there are vital biomarkers that indicate cognitive decline, such as shrinking of brain mass due to the death of brain cells. Observing how these proteins operate within the mitochondria allows researchers to more closely understand how NSCs achieve cell death and result in the shrinking of brain matter.
Through the usage of scRNA-seq, a mouse model was used to take a closer look at the differing types of cells that existed in both younger and older mice. The scientists first began by completing a scRNA-seq of the differing mice to observe how there may be age-related differences in the types of cells within the tissue of the dentate gyrus. Upon inspection, it was observed that the older mice had a higher degree of mitochondrial protein folding stress than the younger mice. To test these differences, they used Sirt7 (an enzyme that is clinically known to reduce mitochondrial protein stress) to target the mRNA of both old and young mice to see how their NSC development is affected upon their addition.
Results showed that younger mice were able to express Sirt7 within their brains and decrease mitochondrial protein stress, while older mice observed no change in levels of mitochondrial protein folding stress. Critically, this study indicates that Sirt7 is expressed in high quantities in the brain of young mice whereas it is minimally expressed in the brain of aged mice, suggesting a strong biological difference in the presence of Sirt7.
I got the opportunity to speak to one of the leading scientists behind the publication, Dr. Danica Chen, to learn more about the significance of the research and ask her about the future of anti-aging research. Dr. Chen is a Principal Investigator within the Nutritional Sciences and Toxicology Department at UC Berkeley that studies aging-associated conditions to understand the ways in which they may be reversible. When asked about the potential of Sirt7 being used as a targeted therapy for anti-aging treatment, Dr. Chen said that “Sirtuins have been attracting lots of interest in anti-aging research because they are enzymes, which is good because that means they are druggable!”
In addition to performing Sirt7 cell sequencing on mice, an exciting find was revealed when observing the effects of induced Sirt7 overexpression in mice and their motor function. In a water maze test, one aged control mouse and one aged mouse that received Sirt7 injections were placed in two identical water mazes and were given a visual cue to follow. The goal was to observe how these mice were able to swim after a flickering target by using memory and spatial recognition. The test revealed how the mice with overexpressed Sirt7 spent a significantly longer time in the quadrant with the light flickers in comparison to the WT mice, who did not demonstrate a preference for the target quadrant while swimming. In simpler terms, the Sirt7-injected mice were better able to remember the queues of the flickering light and keep up with the laser!
One of the final techniques this study used to re-analyze their data and assess quantities of mitochondrial protein stress was to perform an immunohistochemistry staining to isolate a protein called HSP60, which is known for folding protein in the mitochondria. Immunohistochemistry staining is a technique used by biologists to identify a single type of protein in a sample of tissue. In this case, our tissue samples were brain samples of both young and aged mice. Upon completion of staining, it was found that the brains of the older mice contained a larger amount of HSP60 than the younger mice, reaffirming the conclusion that mitochondrial protein-folding stress is present in NSC of the dentate region of the aging brain.
Previous research completed by other scientists has highlighted the role that Sirt7 has played in mitochondrial protein folding, and it’s well known that different classifications of sirtuins have the ability to regulate the development of brain tissue to mitigate cognitive decline. Sirtuins were discovered in a study completed in 1979 in which gene expression was observed in yeast cells, and in the past ten years, there’s been a continuous effort by researchers to discover more about this versatile enzyme that has such a vital role in signaling pathways throughout our bodies.
I wanted to ask Dr. Chen, as one of the founders of the Bay Area Aging Meeting back in 2009, about her thoughts on the booming field of anti-aging–especially in what direction she sees it growing in. Dr. Chen spoke about how “when [she] got into the field 20 years ago, it was a relatively small field” but she’s seen an exponential interest within the scientific community in the past fifteen years, especially within Silicon Valley: “There are so many biotech companies getting into the aging domain, such as Calico, which is a Google company”. As humans’ life expectancies continue to increase with time, it’s vital that scientists inch closer to understanding how our brains may age to optimal health.
