As the body ages, organ function progressively declines and the risk for a wide range of diseases, including cardiovascular disease, cancer, and neurodegenerative diseases increases. Understanding how the body ages is an intense area of research as it could potentially indicate ways to promote healthy aging.
An international research effort by scientists at Baylor College of Medicine, Chan Zuckerberg Biohub San Francisco, Genentech, and collaborating institutions has now generated the first aging fly cell atlas (AFCA), as a detailed characterization of the aging process in 163 distinct cell types in the fruit fly laboratory model organism, Drosophila melanogaster. The team’s in-depth genetic analysis of individual cells revealed that different cell types in the fruit fly body age differently, with each cell type following a process involving cell type-specific patterns of gene expression changes. The researchers suggest that the AFCA will represent a valuable resource for scientists carrying out fruit fly and aging research, as a reference to study aging and age-related diseases, and potentially to evaluate the success of anti-aging strategies.
“A critical observation of this study is that cell type-specific aging patterns in cells can be used to gauge biological age, that is the relative aging status of an organism, independent of its chronological age,” said Heinrich Jasper, PhD, principal fellow at Genentech. “This will provide further insight into factors, such as diets, drugs and diseases, that may change the aging trajectory and hence make an organism ‘younger’ or ‘older’ than its chronological age.” Jasper is co-corresponding author of the team’s published paper in Science, titled “Aging Fly Cell Atlas identifies exhaustive aging features at cellular resolution,” in which the team concluded, “This atlas provides a valuable resource for studying fundamental principles of aging in complex organisms.”
Aging is a natural process that is associated with the gradual decline of tissues in the body, and this process increases the risk of developing various diseases, the authors explained. While the study of aging has a long history, and several aging hypotheses have been proposed, there are still unanswered questions when it comes to understanding the effects of aging on the composition and maintenance of different cell types. For example, the authors wrote, “How does aging affect cell composition and the maintenance of specific cell types? Do different cell types age at the same rate? Can we use one cell type’s transcriptome to predict age? What genes and signaling pathways drive aging in different cell types?”
Hongjie Li, PhD, assistant professor of molecular and human genetics and the Huffington Center on Aging at Baylor, added, “Research has shown that, for instance, some cells like neurons in the brain live longer than cells in the gut lining, which are replaced by new ones often,” Li is also a member of Baylor’s Dan L Duncan Comprehensive Cancer Center.
The fruit fly is a well-known model to study human conditions. “The fruit fly, Drosophila melanogaster, has been at the basis of many key discoveries in genetics, neurobiology, development, and aging,” the authors continued. In fact, about 75% of genes associated with human diseases have functionally similar counterparts in the fly, and many of the age-related functional changes in humans are also observed in flies, “including a decline in motor activity, learning and memory, cardiac function, and fertility,” they continued. “Hence, a proper description of the molecular and genetic basis of the age-related decline in flies should provide an important resource for aging studies not only in flies but also in other organisms.” Li continued, “Our team is interested in better understanding how different cell types age differently, and to that end, we analyzed in detail several biological characteristics of individual cell types as fruit flies aged naturally in the lab.”
The researchers took cell samples from the aging laboratory fruit flies, at 30 days, 50 days and 70 days old. A fly at 70 days old is equivalent to an 80-year-old person. At each time point the team conducted single-nucleus RNA sequencing (snRNA-seq) to analyze gene expression changes in individual cells in different organs. They then compared the results to those of cells in young, five-day-old flies. The team in particular examined four different aging features: cell composition changes, number of differentially expressed genes (DEGs), change in the number of expressed genes, and decline of cell identity. They found that as the flies aged, these features changed as a group according to cell type-specific patterns.
“We found that aging impacts cellular composition across the whole fly,” Li said. Fat body cells were among the cell types that increased in number the most, while muscle cells decreased the most. Neurons, however, did not show major changes in the number of cells during the fruit fly’s life. Li added, “In addition, the analysis of the genes expressed by different cell types in time revealed that fat cells show the largest difference between the number of genes expressed in young versus old fruit flies.”
The researchers found that about 80% of all the cell types analyzed decreased the number of genes expressed, and 20% increased this number. “We plan to study the mechanism of this observation in the future,” said co-first author Tzu-Chiao Lu, PhD, postdoctoral associate in the Huffington Center on Aging.
The team also found that cellular gene expression programs that define cell identity change as the animals age. “For example, compared to the flight muscle identity marker Nig1 in young flies, the marker in older flies is dramatically decreased, while other markers began to appear as the flies grew older,” Li said.
“Our analysis using different aging features provides several key insights,” the team summarized in their paper. “First, different cell types have distinct aging patterns … Second, we observed a divergence in the contribution of individual cell types to a tissue’s aging … Third, the top-ranked cell types include all adipose cells.” This is surprising, they acknowledged, “and we do not fully understand the underlying mechanisms. It may be linked to the fact that these cell types play multiple critical roles in different physiological conditions, such as lipid storage and metabolism, immune responses, and interorgan communication with muscles and gut.”
“We have learned that each of the four aging features we studied measures a different aspect of the cell and that not a single feature applies to all cell types,” Li continued. “Combining all aging features led us to discover unique cell type-specific aging patterns and comparing them revealed useful and interesting findings. For instance, neurons in the brain age slowly, while muscle, fat and liver cells age much faster. Also, cell-type specific aging patterns may vary according to gender.”
Stephen Quake, PhD, the Lee Otterson Professor of Bioengineering and Applied Physics at Stanford University and co-corresponding author of the report, said the new atlas provides a powerful, open-access resource for scientists to better understand the biology of aging. “Through a highly productive collaboration, our team has created an exceptionally detailed map of how gene expression changes with aging across a wide range of cell types in the fly. Since a majority of these genes have similar roles in people, this dataset offers a unique vantage point to begin to decipher why many serious human diseases emerge in later life.” Quake is also head of science at the Chan Zuckerberg Initiative (CZI).
As the authors concluded in their research article summary, the AFCA represents “… an important and timely resource for studying aging and age-related diseases. It has the potential to serve as a reference of whole-organism aging that can be used as a baseline for exploring different age-related diseases and understanding how different longevity perturbations increase life span at a cellular resolution.”
Li continued, “We hope that researchers will explore the possibilities AFAC offers to a variety of scientific fields, including genetics, cell biology and physiology.” The team has developed a user-friendly data portal and provide access via CZI’s CELLxGENE platform. All resources can be accessed at https://hongjielilab.org/afca.