(A) Fidelity of protein synthesis and oxidative protein damage across lifespan. Fidelity and accuracy in protein biosynthesis with chaperone-assisted folding are the cell’s major energy consumers. Although there is a trade-off between efficacy and quality, the essentials of natural selection through reproductive success must be taken into account. While activated mTOR pathway accelerates translation to invest sufficient ATP production, it undesirably decreases the fidelity and increases misfolding that results in reduced protein stability with augmented sensitivity to oxidation. Generally, nature selective process maximises the investment of energy production for parental proteome quality and sexual maturation to ensure the perpetuation of species, whereas the balance between energy supply and fidelity of protein translation, would diminish once reproduction is assured. As such, the fidelity of protein synthesis remains highly preserved at earlier stage of the human lifespan, but starts to decline after the reproductive period around middle adulthood followed with a dramatic decline in late final third of lifespan. In parallel with the decline of fidelity, the increased misfolding of proteins lose resilience to oxidative stress and succumb to oxidised protein damage accumulating with age. In the case of NMRs, the lifelong intrinsic reproductive capacity in these rodents ensures a parental proteome quality throughout the lifespan, where a high fidelity of protein synthesis and low protein damage is consistently maintained during the whole-life trajectories. (B) Loss of stress-induced adaptive homoeostasis with age. In early life, the human system maintains a low baseline activities of stress responsive network (e.g. NRF2/KEAP1 signalling and transcription of its downstream stress-protective genes). Exposure to stressors, such as oxidative stress initiates rapid activation and up-regulation of transcription and translation of cytoprotective and proteasome enzymes to counteract the oxidative stress and protein damage (induced adaptive homoeostasis). The big range between low baseline homoeostasis and high physiological ceiling ensures a large capacity of adaptive homoeostasis to cope with stress variance and maintain health in early life. In middle age, baseline levels of repair activities increase but the physiological ceiling of homoeostasis declines as the ‘wear and tear’ dysfunction across cell, tissue and organ levels (e.g. accumulative protein damage). As a result, stress-induced response is compressed with reduced capacity to maintain adaptive homoeostasis. This range of adaptive homoeostasis between basal and physiological ceiling is further compressed in the later life where a high baseline adaptive homoeostasis is exploited to cope with day-to-day stress perturbations with extremely restricted physiological ceiling. As a result, the organism system eventually loses the capacity of adaptive homoeostasis to counteract any extra stressors and are imposed to increased risk of burden of lifestyle diseases. Abbreviation: KEAP1, Kelch-like ECH-associated protein 1.