Abstract
Organic elements make up 99% of an organism but without the remaining inorganic bioessential elements, termed the metallome, no life could be possible. The metallome is involved in all aspects of life, including charge balance and electrolytic activity, structure and conformation, signaling, acid-base buffering, electron and chemical group transfer, redox catalysis energy storage and biomineralization. Here, we report the evolution with age of the metallome and copper and zinc isotope compositions in five mouse organs. The aging metallome shows a conserved and reproducible fingerprint. By analyzing the metallome in tandem with the phenome, metabolome and proteome, we show networks of interactions that are organ-specific, age-dependent, isotopically-typified and that are associated with a wealth of clinical and molecular traits. We report that the copper isotope composition in liver is age-dependent, extending the existence of aging isotopic clocks beyond bulk organic elements. Furthermore, iron concentration and copper isotope composition relate to predictors of metabolic health, such as body fat percentage and maximum running capacity at the physiological level, and adipogenesis and OXPHOS at the biochemical level. Our results shed light on the metallome as an overlooked omic layer and open perspectives for potentially modulating cellular processes using careful and selective metallome manipulation.
Highlights
Organic elements make up 99% of an organism but without the remaining inorganic bioessential elements, termed the metallome, no life could be possible
The δ65Cu and δ66Zn values are organ-specific, suggesting that isotope fractionation depends on fine, organ-specific processes (Fig. 1c, d)
The δ66Zn value in heart, brain, muscle and liver follows a linear relationship with Zn concentration, a relationship that is known to indicate identical Zn routing in these organs[15], obviously distinct in kidneys where glomerular filtration probably drives isotopic fractionation through a distillation process[16] (Fig. 1c)
Summary
The metallome and isotope compositions fingerprints are organ-specific. We measured the metallome (K, Mg, Na, P, S, Ca, Fe, Cu, Rb, Zn, Se, Co, Mo, and Cd) and the Cu and Zn stable isotope compositions (denoted hereafter δ65Cu and δ66Zn, respectively) in five organs (brain, heart, kidney, liver, and muscle, Supplementary data 1 and table S1) of 49 C57BL/6 male mice aged 6-, 16-, and 24-months old (mo) (Fig. 1a). 1f and S2), suggesting unprecedented evidence of disrupted K metabolism in old mice These results confirm the value of the metallome as a biomarker for aging[14], but our data extend this observation to isotope compositions, notably the decrease of the liver δ65Cu value during aging (Fig. 1f). While increased Cu concentration[33] and isotope composition[4,34,35] have been previously associated with metabolic activity and growth of tumors, our study shows that δ65Cu may be a more general indicator of metabolic fitness These liver metal concentrations may not be causal in metabolic fitness, but rather represent a biomarker of liver health in metabolically healthy animals, as opposed to mildly obese or diabetic animals which develop liver dysfunction. Subtle variations in metal concentrations are conserved across studies and associated with markers of metabolic health at both the physiological (body weight, fat percentage, and insulin resistance in the IPGTT) and biochemical levels (OXPHOS, lipid synthesis among others). The high reproducibility of metallomics suggests that changes in metal concentration may represent a source of reliable and affordable biomarkers of organismal, tissular, cellular, and subcellular aging and metabolism
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