Revisiting the limitation to with ageing: is mitochondrial (dys)function the key?

Attaining a high capacity for whole-body oxygen consumption () is required for elite endurance performance, while a low is a strong predictor for all-cause mortality, highlighting the significance of this measurement across the entire spectrum of health. A coordinated delivery of oxygen to the periphery, in addition to the ability to use that oxygen as an electron acceptor to produce ATP within mitochondria, are the core parameters of an individual's . The physiological factors ‘upstream’ of mitochondrial oxygen consumption () that may affect include: (1) pulmonary diffusing capacity, (2) maximal cardiac output, and (3) oxygen carrying capacity of the blood (cf. Tonkonogi & Sahlin, 1997). It is well-established that reductions in each of these mechanisms exist with ageing; however, possible ‘downstream’ limitations within the skeletal muscle of older individuals remain elusive. Though the literature has historically demonstrated a correlation between and mitochondrial content and respiratory function in healthy individuals (Tonkonogi & Sahlin, 1997), more recent work has revealed that this long-standing relationship may not be as strong as previously postulated, specifically in the context of analysing respiration in permeabilized muscle fibres (PMF) throughout the lifespan. It is within this context that a recent publication from Zhang et al. (2021) in The Journal of Physiology re-evaluated the possibility that reductions in mitochondrial respiratory capacity contribute to age-associated declines in . The impact of ageing on skeletal muscle mitochondrial biology is a topic that has been closely examined in recent years. The recent publication by Zhang et al. (2021) aimed to evaluate the effects of age and sex on whole-body cardiorespiratory fitness, skeletal muscle mitochondrial physiology and habitual physical activity in young and old adults. The study involved 23 young (20–35 years) and 52 old (65–85 years) healthy individuals who did not participate in any structured exercise training at the time of the study. The subjects were fitted with a 3-axis accelerometer which was worn during waking hours for 14 days, followed by a percutaneous biopsy of the vastus lateralis, succeeding an overnight fast, for quantification of mitochondrial function in permeabilized fibres. Measurements from the outlined tests revealed that: (1) drops precipitously with age; (2) skeletal muscle mitochondrial oxygen consumption is maintained with age in the presence of saturating concentrations of mitochondrial oxidative phosphorylation (OXPHOS) substrates and oxygen; and (3) daily duration of moderate to vigorous physical activity decreases with age despite maintenance of total daily step counts. The present study offers an interesting perspective into the controversy associated with ageing and skeletal muscle mitochondrial physiology. The investigators attempt to demonstrate that the relationship between mitochondrial oxidative capacity and falls apart with age, yet it remains uncertain if this relationship even exists within the younger cohort. Along these lines, extrapolated data from the focus paper demonstrates a weak correlation between and in the young subjects (Fig. 1A). It should also be noted that the slope of regression appears to be driven by a single subject (highlighted in Fig. 1A). Upon further analysis, the coefficient of determination, whereby the proportion of variance from can be predicted from is estimated to be 0.29. This indicates that ∼70% of cannot be explained by mitochondrial respiratory function in the younger cohort. Though speculative, it is possible that the ambiguity within this data set is a result of the low training status of the participants, as it is well recognized that mitochondrial content and function increase as an adaptation to exercise, and increases with training (cf. Tonkonogi & Sahlin, 1997). However, the caveat to this argument is that various components within the cardiovascular system can also be improved as part of the training process independently of age, and therefore the increased mitochondrial oxygen consumption associated with training cannot be the only determinant of increases to . In line with this, it is possible to improve in even the most trained individuals with exogenous enhancement of oxygen availability to the working muscle, as a reserve in mitochondrial respiratory capacity exists (Desler et al. 2012). Given that the present work assessed mitochondrial oxygen consumption in the presence of saturating concentrations of OXPHOS substrates, it is not surprising that appears to be maintained throughout the lifespan, while precipitously decreases. Analysis of data from the older cohort yields an R2 estimate of 0.07 (Fig. 1B), indicating that the original relationship between and becomes even weaker with age when assessed in PMF in the presence of saturating concentrations of OXPHOS substrates. Regression analyses were used to evaluate the relationship between cardiovascular fitness () and mitochondrial oxidative capacity () in extrapolated data from Zhang et al. (2021). There appears to be a weak relationship between these parameters in young subjects (A); however, the power of this correlation is almost entirely diminished in older subjects (B). Blue symbols are males and red symbols are females. R2 is averaged for both males and females. While the present data highlights a weak relationship between mitochondrial respiratory capacity and age-associated declines in , previous findings suggest that the use of saturating concentrations of OXPHOS substrates and oxygen may not be entirely indicative of in vivo biological processes. Specifically, findings from Holloway et al. (2018) demonstrate various indices of mitochondrial function to be maintained throughout the lifespan when assessed in the presence of saturating concentrations of ADP and oxygen; however, when assessed in the presence of non-saturating ADP concentrations, respiration decreased while mitochondrial ROS production increased, suggesting a reduction in the sensitivity of mitochondria for ADP (Holloway et al. 2018). The latter findings are in accordance with several in vivo reports of mitochondrial function using nuclear magnetic resonance spectroscopy (NMR), which have demonstrated a reduction in mitochondrial function through the lifespan (cf. Fitzgerald et al. 2016). While this is not a universal finding, as original NMR work found no impairments to mitochondrial function with age (cf. Fitzgerald et al. 2016), these data highlight the potential importance of the concentrations of OXPHOS substrates added to permeabilized tissue when assessing mitochondrial respiratory capacity ex vivo, and the relevance to in vivo biological processes. Nonetheless, results from the current work provide further evidence that either: (1) saturating PMF with OXPHOS substrates and oxygen is not representative of in vivo mitochondrial bioenergetics, or (2) mitochondrial content and function is not the limitation to , but rather stems from an individual's ability to deliver and extract oxygen from the working muscle. While the principal cause of this age-related decline of remains elusive, the authors of the focus paper speculate that impairments to cardiovascular function play an important role. To test this supposition, it would be necessary to increase the cardiac output of older subjects to ‘re-establish’ a higher . Follow-up work is required, whereby investigators (1) induce plasma volume expansion in older subjects to increase their cardiac output, or (2) have older subjects complete a single leg cycling test. While it should be noted that infusing blood to achieve plasma volume expansion is relatively invasive, the associated increase in cardiac output and the enhanced ability to deliver blood to myocytes may be an important next step in elucidating the mechanism behind the decrease in that is correlated with age. Considering this limitation, the latter option whereby subjects complete single-leg exercise may present as a more realistic alternative. Rather than diverting cardiac output to both legs, single-leg exercise allows for cardiac output to be delivered to an individual leg, increasing blood flow to the working limb. If the of older individuals is normalized in this situation it would help to confirm that oxygen delivery is the limitation to with ageing. However, if increased blood perfusion does not increase in older individuals, this would strongly support the interpretation that a reduction in either mitochondrial oxidative metabolism, or oxygen extraction associated with age-induced capillary rarefaction, contributes to the decline in across the lifespan. Overall, Zhang et al. (2021) have offered valuable insights into the relationship between and mitochondrial oxygen consumption. While further research in this area could contribute to the current understanding of the impact of age on , the results reported in the present work provide further evidence that the use of PMF in the presence of saturating concentrations of OXPHOS substrates and oxygen to quantify mitochondrial oxygen consumption has little relevance to whole-body biological processes. Though it is evident that declines throughout the lifespan, the source of these alterations remains uncertain. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. All authors: conception or design of the work; acquisition or analysis or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. V.P.B. (Canadian Graduate Scholarship – Master's) and P.A.B. (Canadian Graduate Scholarship – Doctoral) hold scholarships from the Natural Sciences and Engineering Research Council of Canada.

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