Proteomics and metabolomics in ageing research: from biomarkers to systems biology

Abstract

Age is the single greatest risk factor for a wide range of diseases, and as the mean age of human populations grows steadily older, the impact of this risk factor grows as well. Laboratory studies on the basic biology of ageing have shed light on numerous genetic pathways that have strong effects on lifespan. However, we still do not know the degree to which the pathways that affect ageing in the lab also influence variation in rates of ageing and age-related disease in human populations. Similarly, despite considerable effort, we have yet to identify reliable and reproducible ‘biomarkers’, which are predictors of one’s biological as opposed to chronological age. One challenge lies in the enormous mechanistic distance between genotype and downstream ageing phenotypes. Here, we consider the power of studying ‘endophenotypes’ in the context of ageing. Endophenotypes are the various molecular domains that exist at intermediate levels of organization between the genotype and phenotype. We focus our attention specifically on proteins and metabolites. Proteomic and metabolomic profiling has the potential to help identify the underlying causal mechanisms that link genotype to phenotype. We present a brief review of proteomics and metabolomics in ageing research with a focus on the potential of a systems biology and network-centric perspective in geroscience. While network analyses to study ageing utilizing proteomics and metabolomics are in their infancy, they may be the powerful model needed to discover underlying biological processes that influence natural variation in ageing, age-related disease, and longevity.

Measuring biological aging in humans: A quest

“…Senescence has been studied successfully in T lymphocytes, skin, and intramuscular fat, and high-throughput methods will be available soon (Evangelou et al, 2016;Lozano-Torres et al, 2017). In addition, specific patterns of circulating proteins may exist that indirectly estimate the burden of senescence (Angelini et al, 2017;Hoffman, Lyu, Pletcher, & Promislow, 2017;Kadota et al, 2018;Menni et al, 2014;Tanaka et al, 2018;Yousefzadeh et al, 2017). Similarly, measures of autophagy are routinely used in mammalian studies and should be applicable to humans (Klionsky, 2014;Klionsky, Cuervo, & Seglen, 2007;Menzies, Moreau, Puri, Renna, & Rubinsztein, 2012).…”

The Aging Metabolome—Biomarkers to Hub Metabolites

“…Figure briefly summarizes metabolomics workflows for analysis of biofluids and tissues using mass spectrometric approaches. These workflows have already been reviewed elsewhere [ 13–18 ] and are beyond the scope of the current review.…”

“…This systems approach to metabolism is expected to illuminate the underlying mechanisms that mediate aging and aging‐associated diseases. Although metabolites can be measured comprehensively across the metabolic network using metabolomics technologies, [ 13,14 ] specific subsets of metabolites within the network have emerged as particularly significant mediators and targets of anti‐aging interventions (nicotinamide adenine dinucleotide [NAD + ], reduced nicotinamide dinucleotide phosphate [NADPH], α‐ketoglutarate [αKG], and β‐hydroxybutyrate [βHB]), these will be further elucidated in this review. Here we discuss MS‐based metabolomics enabled aging biomarkers, followed by analysis of significant nodes in the metabolome that are emerging in the context of aging biology.…”

Aging Biomarkers: From Functional Tests to Multi‐Omics Approaches

“…The magnitude of genetic contribution to human variation in aging is still debated, varying from around 15% to 30%, [ 91 ] but probably overestimated due to assortative mating in accordance to a recent suggestion [ 92 ] ; the population specificity contributes to moderate convergence between research results, since genes that affect human aging in one population may not be replicated in another. [ 93 ]…”

“…The advantages of metabolomics in aging research over other omics approaches are enhanced sensitivity and predictability to the physiological state of the body, as well as the potential rapid responsiveness to intervention (diet, lifestyle, and drugs). [ 93 ] However, similar to proteomics, current metabolomics analytical methods cover only a limited fraction of circulating metabolites in a single experiment. [ 90 ]…”