“Ageing defies easy definition, at least in biological terms. It is not merely the passage of time. It is the manifestation of biological events that occur over a span of time. The biology of ageing has come a long way from being the domain of quacks and merchandisers bent on exploiting people’s vanity to sell cosmetic repairs. Today, it is one of the last major biological frontiers” (Hayflick, 1994).

In recent decades, researchers have established new frontiers in our understanding of ageing and the biological processes that underpin it. Ageing has been confirmed as a time-related progressive loss of cellular functions, and the deterioration of the physiological systems necessary for survival and fertility (Amorim et al., 2022; Barresi and Gilbert, 2000). It is also clear that ageing is universal (it occurs in all members of the same species), intrinsic (its causes are endogenous, not depending on external factors), progressive (the changes occur gradually throughout life), and deleterious (the events related to the ageing process are harmful) (Hayflick, 1994, 1998; Strehler, 1985). Despite this, continued improvements in medical care and standards of living have contributed to global life expectancy increasing by up to 30 years throughout the 20th century (Fig. 1a) (Christensen et al., 2009). When coupled with the declining fertility rates seen in many regions of the world, the number and proportion of older adults has increased dramatically; the greatest increase has been in the number of adults aged 85 and above (Christensen et al., 2009) (Fig. 1b). This increasing probability of prolonged survival brings considerable social, economic, and health impacts. In particular, the prevalence of many chronic diseases, such as type 2 diabetes, cardiovascular disease, cancer, frailty, sarcopenia, and dementia, increases with age (Niccoli and Partridge, 2012).

Ageing induces physiological changes in all organ systems (Fig. 1c), which coincide with age-related reductions in physical function and resting metabolic rate (McMurray et al., 2014). Indeed, a major consequence of ageing is the progressive decline in skeletal muscle mass and strength, which decline by ∼ 1% per year from middle-age (40–65 y), and which can significantly increase the risk of injury and limit the quality of life in older adults (Bauer et al., 2019; Wilkinson et al., 2018). Muscle strength has also been shown to be inversely and independently associated with rates of all-cause mortality (Ruiz et al., 2008), highlighting the importance of maintaining skeletal muscle function with age (McLeod et al., 2016). Maximal oxygen consumption (V˙O2max), a marker of cardiorespiratory fitness and one of the strongest predictors of mortality, also begins to decline after ∼ 30 years of age (Hawkins and Wiswell, 2003; Wei et al., 1999); this decline is not linear but accelerates dramatically with each successive decade (Fleg et al., 2005).

An individual's V˙O2max is determined by both central (i.e., cardiovascular and respiratory systems) and peripheral factors (e.g., skeletal muscle capillary networks and mitochondria) that affect the delivery, extraction, and utilisation of oxygen in skeletal muscle (Wagner, 1996). Mitochondria are the primary consumers of oxygen, which they use for energy production via oxidative phosphorylation. As such, considerable interest has been given to the role(s) of mitochondria in the complex aetiology underpinning ageing (Coen et al., 2018). Detrimental alterations to mitochondria have been identified as a hallmark of ageing (López-Otín et al., 2013; López-Otín et al., 2023), and some age-related declines in skeletal muscle function may be mediated by changes in mitochondrial characteristics (Gonzalez-Freire et al., 2018). Similar changes in mitochondrial characteristics have also been proposed to contribute to the development of diseases associated with ageing, such as sarcopenia and dementia (Amorim et al., 2022).

To tackle the growing health and economic burdens associated with ageing populations, maintaining good health in later life has become a major research priority (Moreno-Agostino et al., 2020). Accordingly, the World Health Organization (WHO) has called for urgent and comprehensive public health action on population ageing, and provided a framework for the study and promotion of healthy ageing (which was defined as the “process of developing and maintaining the functional ability that will enable older people to do the things that matter to them”) (World Health Organization, 2015). Regular physical activity and exercise2 are integral to healthy ageing. Exercise training is a well-established intervention for improving cardiorespiratory fitness, metabolic health, muscle mass, and strength (Pedersen and Saltin, 2015). Furthermore, cardiorespiratory exercise training3 provides a potent stimulus for many skeletal muscle mitochondrial adaptations (Bishop et al., 2019; Granata et al., 2018a, 2021, 2018b; MacInnis and Gibala, 2017). In addition, resistance exercise, in which skeletal muscles exert force to push or pull against resistance, has also been shown to promote mitochondrial adaptations (Botella et al., 2023; Porter et al., 2015), particularly in older populations (Robinson et al., 2017). As such, lifelong adherence to regular physical activity and exercise likely impacts age-related effects on mitochondrial characteristics. However, in many studies to date, participants’ habitual physical activity levels or training status have not been adequately described or controlled. Thus, the respective effects of ageing and reduced physical activity (a common lifestyle characteristic in older populations (Cunningham et al., 2020)) on the mitochondrial characteristics of older adults remains a subject of considerable debate.

This review aims to summarise our current understanding and knowledge gaps of age-related changes to mitochondrial characteristics within skeletal muscle (as well as to provide some novel insights into brain mitochondria), and to propose avenues of future research and targeted interventions. Furthermore, where possible, we incorporate discussions of the modifying effects of physical activity, exercise, and training status, to reported age-related changes in mitochondrial characteristics.