Aging, VO2 max, entropy, and COVID-19.

The decline in human performance with age at 5000 m, an athletic event requiring high VO2 max, is remarkably precise, and unavoidable, and related to entropy, even at an individual level. Women and men show an identical age-related decline, up to ~100 years old. The precision of the decline shows the limitations for therapy of aging. Mortality incidence for COVID-19 shows a similar relationship. We propose that initial VO2 max has a critical role in COVID sensitivity because of the direct relationship of disease severity with oxygen use, and the parallel decline in aging.

Introduction

Drugs to slow aging have always been a mirage for humanity, and never really ratified because of enormous individual variability and a failure for drugs to have robust effects, despite more than 100 companies being engaged in aging research. However, parameters which do show a remarkable precision in some aspects of human decline are becoming apparent. Such parameters could have great use for pharmacological and lifestyle interventions to delay aging, because they would allow interventions to be more precisely targeted. We review the remarkably precise decline of human performance with age, VO2 max, and the relationship with disease susceptibility, confirming that the decline relates to entropy, and that humans are already highly optimized for aging. This optimization limits possibilities for intervention and also the relevance of animal models, where aging may not be so optimized.

Since, Gompertz, in 1825, first defined age-dependent mortality, age-related phenomena can be partially quantified.[1] Human beings are exceptional, in having a long life, but with a high metabolic rate and large brain compared to other primates, driven by evolution to run and hunt and by a necessity for social interaction and tool making.[23] Metabolomic studies have shown that this increase in human performance, and a long life has been achieved by mitochondrial adaptation and more efficient lipid metabolism in brain and muscle.[45] These findings are under-estimated in aging research because many therapeutic interventions for molecular targets are proposed from studies in mice or other species, but these may already have been optimized in human beings, to allow our aging and energetic lifestyle.

Age-related frailty

Age-related frailty has also been shown to be associated with a deterioration in lipid metabolism, as assessed by metabolomics showing disruption of acylcarnitine metabolism in mitochondria.[6] In this respect, enveloped viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) or dengue virus, change the metabolism of host cells in a similar way in order to pervert cell metabolism to further infection and to create membranes for their envelopes[7] Age-related severity is a striking aspect of COVID-19,[8] and Spiegelhalter[9] has put this into context showing the exponential relationship of COVID-induced mortality with age and frailty.

However, functional decline among individuals is disparate, depending upon individual genetics, upbringing and environment, obfuscating definition of precision in the aging process. To minimize this, we have collated previously the age-related decline in human performance in multiple sports and activities using age-related world best performances, to find astonishingly precise systematic declines described by a single exponential, accounting up to 99% of total variance.[10] This is because, by definition, age-related world best performances will be by apparently healthy individuals, selected from the best of humanity, in any particular activity: it is the ultimate human performance frontier.

Precise decline in human performance

We thus analyzed running speed at 5000 m, in meters/sec, for the world records of men and women for each age [Figure 1a], because performance at 5000 m is particularly well correlated to VO2 max,[11] and hence to oxidative capacity. Figure 1b shows the decline as a percentage of absolute world best speed for men and women: the decline for men and women is an almost exact overlay and fits the single exponential previously described.[10] This shows that the decline in maximal human performance is precisely defined, and that both men and women show a similar decline. Taking world best performances as the endpoint uses the best examples of humanity, presumably disease free, thereby reducing individual variability. Furthermore, we have previously examined age-related decline in multiple sports, and there has been no real improvement over the last 30 years,[10] indicating that these performances reflect an absolute capacity for homo sapiens.

Figure 1

(a) Average speed for age-related world records at 5000 m for men, women, and for M Spedding expressed in meters/sec. (b) Speed expressed as a percentage of world absolute best performance for men and women, and for M Spedding as percentage of personal best. Note the almost exact superimposition of curves. (b) Also the age-dependency of mortality for COVID-19 in the USA, and in Italy. The age dependency for deaths from influenza and pneumonia in the USA in 2018 (Flu) is also shown. Data are from the ARRS database (https://arrs.run/SA_O5K.htm) and M Spedding race records, and Centers for Disease Control and Prevention (cdc.gov)

Similarly, racehorses, greyhounds, mice, and even Caenorhabditis elegans, show a similar age-related decline, when related to lifespan.[12] It is a key aspect of life, representing entropy and the cumulative aspects on aging. Hayflick[1314] has argued strongly that the decline represents entropy, with major implications for health care. Human beings seem to be optimized metabolically, as they have extended lifespan compared to nearly all other animals, and this is a very metabolically active life, whereas some species age slowly by reducing cellular activity. The precision of decline among the best human athletes implies that there is an extreme precision in the aging process, when disease is not present. The consequence is that it may be difficult to further improve absolute life expectancy (other than that limited by diseases), especially as there have been no changes in age-related decline over the last decades despite increased participation in master athletics.[15] Furthermore, although men have evolved to have higher maximal running speed compared with women, this sex differential is not seen in greyhounds and horses.[16] [Figure 1b] shows quite clearly that the rate of decline in running speed for men and women is identical with age, so the entropy changes with aging cannot be related to the evolutionary factors favoring male running speed. As the decline describes world records, different athletes contribute to the data, so it is unclear whether individuals show the same precise decline. Here, we show that the decline in performance of one of the authors, at 5000 m (M Spedding, who has competed at 5000 m for 50 years at ~15% of age-related world best), fits the same exponential, despite his best efforts [Figure 1]. Thus, the decline in performance is a general phenomenon, but its extreme precision may allow ways of analyzing drugs claimed to slow aging, if the right parameters can be examined. Nevertheless, even highly motivated individuals show the same decline as world best performances, showing how inescapable the decline is, particularly in an event demanding a high VO2 max, and therefore good mitochondrial coupling.

COVID-19 and VO2 max

In Figure 1b, we also show the percentage of deaths, related to age, for COVID-19 in the US and Italy, and for influenza and pneumonia (in 2018), in the US. The age-related mortality for COVID-19 increases in parallel to the age-related decline in athletic performance. Although the exact relationship between death of athletes and their athletic decline is unclear, athletic excellence is associated with ~7-year additional longevity.[17] Nevertheless, death for patients with COVID-19 (or influenza) increases when substantial decline in physical performance occurs either through aging or through physical inactivity. In France, for example, of 88574 total deaths, 25174 were in nursing homes, 28.4%, as at 8/3/2021). Nursing home residents have very low VO2 max values (VO2 max 13 ± 1, at 73 ± 5 years old)[18] which may be associated with their sensitivity to COVID-19. For reference, the cross-country skier Bjorn Daehlie had a VO2 max of 96 ml/kg/min, the highest recorded, whereas untrained males are normally between 30 and 40 ml/kg/min and M Spedding even at >70 years old has a VO2 max ~45. VO2 max decline with age is 4–5 ml/kg/min/decade in the elderly with a loss of independence at ~18 ml/kg/min for men and 15 ml/kg/min for women; a program of aerobic exercise could slow or reduce “biological age” by ~10 years.[1920] The Baltimore Longitudinal Study of Aging showed that mitochondrial respiratory capacity (in permeabilized human muscle fibers from men aged 24–91 years) was directly related to VO2 max and muscle strength and walking ability:[21] This study, using transcriptomics, also showed that mitochondrial genes were downregulated more than other genes by aging, and there was an inverse trend between mitochondrial efficiency and body mass index. Muscle strength has been shown to be the most relevant indication of aging, analyzing women who were nonathletes.[22]

However, the pandemic has had a negative effect on physical activity all over the world as defined by steps taken during confinements (https://blog.fitbit.com/COVID-19-global-activity): In Europe, weekly step counts declined by 7%–38% depending on the country. However, patients developing COVID-19 have severe problems with oxygen saturation, and astonishingly low levels of oxygen saturation have been reported in 20%–40% of patients, with silent hypoxia, sometimes without respiratory distress (~50%–80% saturation, when normal saturation is >95%).[23] Furthermore, a 6-min walk test can cause further drops in oxygen saturation in patients with a significant viral load. The mechanism while still obscure has been reviewed,[23] but it seems evident that patients who already have very low VO2 max would be more at risk, having a much lower margin.

Metabolism and mitochondria

There is substantial evidence that SARS-CoV-2 is associated with metabolic changes and lipid metabolism in order to synthesize new viral envelopes and from direct mitochondrial effects.[24] The recovery from SARS-CoV-1 may be long; even 12 years later, severe changes in lipid metabolism were still present, as assessed by acylcarnitine metabolism, directly associated with physical decline and frailty.[25] Lipid metabolism is critical to athletic performance and was a major aspect differentiating human evolution. Humans differ from other primates in their lipidome and in lipid metabolism.[26] Furthermore, sialic acids, and glycosphingolipids, including the neurotrophin GM1 involved in neuromuscular function, are targets for influenza and coronaviruses. Specific mutations in these sialic acids were critical for human evolution ~2.5 million years ago, compared with other primates,[27] a time when humans were evolving to run, changing metabolism, and developing bigger brains over the next 1.5 million years.[3] Thus, lipid metabolism, and VO2 max, may be a key aspect of the inverse relationship between athletic performance and susceptibility to COVID-19. Indeed, there are distinct parallels to susceptibility to COVID-19 and poor athletic performance at 5000 m, as the severity of illness requires a dose-dependent increase in oxygen delivery, and obesity is a factor of risk. In contrast, high-level performance at 5000 m requires a high VO2 max and is inversely related to obesity. The velocity at VO2 max is strongly related to running performance.[28] Furthermore, VO2 max is directly related to the density of mitochondrial cristae which is increased with endurance training.[29] Exercise training upregulates mitochondrial complex 1 which associates into “supercomplexes,” thereby increasing mitochondrial efficacy. Muscle lactate produced by exercise increases muscle triglyceride levels, lipid biosynthesis (PPAR- g and SREBP-1C), and mitochondrial synthesis markers (PGC-1 a).[30] In contrast, sarcopenia is associated with a decline in mitochondrial mass and energy efficiency.[3132] Recent evidence also shows that mitochondrial-associated membranes (MAMs) from the endoplasmic reticulum (ER) are part of the interactome of the nsp2 and nsp4 proteins from SARS-CoV-1 and SARS-CoV-2.[2433] Enveloped viruses accumulate in ER, prior to budding out, creating their envelopes from ER membranes, massively disorganizing ER and MAM,[34] thereby negatively affecting mitochondrial function [Figure 2], and hence cellular metabolism and oxygen use. Glycosphingolipids, related to ceramide, which are critical for creating the glycocalyx on the cellular surface, are synthesized in the ER, and these are essential for viral replication, which occurs in the ER[35] [Figure 2]. Shifts in glycosphingolipid patterns have been shown to alter multiple other age-related metabolic pathways in the largest metabolic study to date of aging in the mouse brain.[36] Thus, viral infections and aging may converge on specific metabolic pathways.

Figure 2

Progression of an enveloped virus replication (dengue virus) in C6/36 cells, with a time-dependent increase in viral replication, association of the viral particles with (endoplasmic reticulum), and its disruption, in creating viral envelopes, within membrane packets and also showing tubular structures (T). Reproduced with permission from Junjhon et al.[34] This major disruption of endoplasmic reticulum will also affect mitochondrial-associated membranes, particularly with severe acute respiratory syndrome coronavirus 2 (see text)

Endemic COVID-19 shortens overall human life expectancy, as exposure of people who are metabolically compromised could be fatal.[37] Thus, men in the USA had a loss of life expectancy from birth from 2019 to 2020 of 2.1 years, although there is considerable variability between countries[38] and also within the USA, with socially disadvantaged groups losing up to three times the number of years of life expectancy, perhaps due to less fitness and increased obesity.[39]

Propositions

Maintaining physical fitness, and VO2 max, may therefore be a simple means for individuals to maintain health. Any exercise may be beneficial, but one particular form of exercise has had a remarkable success, although not tried yet in India. This article has pointed out the particular benefit of 5000M, which by being a short distance, is possible for untrained people to do. Throughout the world, parkruns of 5000 m are very simple events, freely available to anyone, where once a week (usually at 9 am on a Saturday) people may walk or run a 5000 m course, which has had a remarkable success in bringing sport to all, in 730 locations in 22 countries with >2 million finishers in 34 million participations with >170 million km run or walked (https://www.parkrun.com/). An Indian, Fauja Singh, has the best age-related parkrun performance with 38 min 34 s at 100 years old [Figure 1a], compared with the absolute world best of Joshua Cheptegei for 5000 m with 12 min 35 s. Singh has set nearly all the athletic age records for running, over 100–105 years old. He attributed his longevity to no smoking and alcohol, simple vegetarian diet (phulka, dal, green vegetables, yogurt and milk, and no fried food), and lots of water and tea. As exercise is the simplest and most powerful way of increasing VO2 max, with benefits for general health, obesity, depression, and type 2 diabetes, then, such events may be a simple aid to health for India and also reduce the complications following infection with SARS-CoV-2 for people who have benefitted from them.

Conclusion

We consider that aging is a consequence of entropy, with multiple changes involved, but with a precise decline in athletic performance, related to VO2 max, and cellular metabolism. The very precise nature of this decline indicates that it is inescapable, particularly as world best age-related athletic performances have been the objective of many individuals, from all around the world, and men and women are equally affected. This decline in performance may due to entropy, in a disintegrating system, and parallels greater susceptibility to COVID-19 in at-risk individuals, where VO2 max is low, as it is in the aged, or in nursing homes. Thus, maintaining physical fitness may reduce the complications of COVID-19, and is one of the few proven factors offsetting aging.[19]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.