Aging is a complex biological phenomenon that results in functional decline across tissues and organ systems (López-Otín et al., 2013). Age is one of the most significant contributors to disease risk (Kennedy et al., 2014), and the aging process is influenced by a variety of genetic and environmental factors at the tissue and organismal level (Tian et al., 2023; Nie et al., 2022; Kuo et al., 2022). The application of omics technologies in recent years has led to unprecedented insights into the complex biology of aging (Rutledge et al., 2022). Bulk and single-cell transcriptomic analyses of mouse tissues across the lifespan have shown that aging tempo and trajectory, as indicated by tissue transcriptomic signatures, varies widely across tissues (Schaum et al., 2020; Zhang et al., 2021; Almanzar et al., 2020). Remarkably, many of the transcriptomic signatures of aging across tissues can be significantly reversed by caloric restriction or rejuvenated by the transfusion of young blood (Pálovics et al., 2022; Ma et al., 2020). Large-scale proteomic analyses of human plasma also reveal distinct waves of changes across the lifespan, which are associated with distinct biological pathways and affect age-related phenotypic traits and diseases (Lehallier et al., 2019; Oh et al., 2023).
Despite enormous progress, there is no consensus regarding the mechanisms underlying aging at the cellular or tissue level. Although many non-mutually exclusive hypotheses have been put forth to explain the root cause of aging – oxidative damage, genomic instability, epigenetic changes, loss of proteostasis, mitochondrial dysfunction, DNA damage, telomere shortening, cellular senescence, stem cell exhaustion – it remains a major challenge to distinguish between the driver and passenger mechanisms of aging (de Magalhães, 2024). Nevertheless, efforts to understand the proximal and ultimate cause of aging will facilitate development of therapeutics aimed to improve healthy aging (Kaeberlein et al., 2015; Campisi et al., 2019).
In the present study, we focused on aging from a mitochondrial perspective, as this organelle is known to play an important role in the aging process (Jang et al., 2018; Lima et al., 2022; Lanza and Nair, 2010; Sun et al., 2016). Mitochondria supply the bulk of the energy needed to maintain tissue health and repair tissue damage, and their function tends to decline with age. Over time, damage accumulates in mitochondrial DNA, proteins, and lipids, which compromises their functional integrity and leads to dysregulated metabolism and increased oxidative stress. Recent transcriptomic analyses have highlighted major reductions in electron transport chain gene expression across the lifespan (Schaum et al., 2020), and these changes can be significantly reversed by the transfusion of young blood into older mice (Pálovics et al., 2022). Aging-associated reduction in mitochondrial OXPHOS gene expression appears to be conserved between human, mouse, fly, and worm (Zahn et al., 2007). Accordingly, mitochondrial dysfunction has been implicated in various age-related diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic syndromes (Haas, 2019). Boosting mitochondrial health has been shown to delay age-related decline in organ function (Foote et al., 2018; Lima et al., 2023; Chiao et al., 2020; Nilsson and Tarnopolsky, 2019).
Given the central role of mitochondria in tissue health, we aimed to address the extent and magnitude of aging-induced changes in mitochondrial function across tissues and organ systems. Although many studies have examined mitochondrial respiratory capacity in various tissues, the scale was limited in that only a very small number of tissues could be interrogated at the same time. This is largely due to the inherent low-throughput method of assessing respiration which requires freshly isolated mitochondria or cells from tissues (Salabei et al., 2014). Consequently, it was not previously feasible to have a comprehensive and systems-level analysis of mitochondrial function across many tissues and the lifespan.
This barrier, however, has been recently overcome. An innovative method by Acin-Perez and coworkers has made it possible to now assess mitochondrial function in previously frozen tissues (Acin-Perez et al., 2020). This new method circumvents the need to isolate mitochondria at the time of tissue harvest, allowing many tissues to be collected, frozen, and assayed at a later time. We adopted the new method in a standardized workflow to profile mitochondrial activity in 33 tissues from young and old mice of both sexes. The dataset consists of a total of 1320 tissue samples from 40 mice and 3960 high-resolution respirometry assays encompassing three technical replicates. Our study represents the largest and the most comprehensive tissue respirometry analysis to date. Our data provide an unprecedented view on the variations and changes in mitochondrial functional capacity across tissues, sex, and age, thus informing ongoing studies on the causes and consequences of aging.