Metabolomics and aging

As life expectancy has risen steadily over the last years and
diseasefree aging is more and more challenging, understanding the
complexity of age and aging is of great importance. Metabolomics is
one of the novel approaches in systems biology with high potential
to deliver answers to these questions. However, only a few
metabolic studies based on large samples are available so far. In
this thesis, I present results from two population-based studies,
the German KORA Follow-Up 4 (KORA F4) study as a discovery cohort
with a sample of 1,038 female and 1,124 male healthy participants
(32–81 years) and 724 healthy females from UK Adult Twin Registry
(TwinsUK) as replication. Targeted metabolomics of fasting serum
samples with flow injection analysis coupled with tandem mass
spectrometry (FIA-MS/MS) positively quantified 131 metabolites
after stringent quality control. Among these, 71 and 34 metabolites
were significantly associated with age in females and males,
respectively, after adjustment for body mass index (BMI), which is
highly correlated (r=0.9) with age. These results indicate that
metabolic profiles are age dependent and sex specific. Then, a set
of the 12 most age-discriminative, independent metabolites was
identified in women with an approach based on random forest and
stepwise variable selection. This set showed highly significant
differences between subjects aged 32–51 years and 52–77 (p-values
range 1.3E-09 – 1.9E-46, significance threshold p=0.004). Ten out
of these 12 metabolites replicated in unrelated females from the
TwinsUK study, including five metabolites the concentrations of
which increased with age (C12:1, C18:1, sphingomyelin (SM) C16:1,
SM C18:1 and phosphatidylcholine (PC) aa C28:1), while histidine
decreased gradually. Three glycerophospholipids (PC ae C42:4, PC ae
C42:5, PC ae C44:4) showed declines around the age of 51 years.
Meta-analysis of both studies gave virtually the same results as
KORA alone. These observations might reflect many different
processes of aging such as incomplete mitochondrial fatty acid
oxidation, counteracting oxidative stress, and changes in vascular
functions. The identification of these ten age-related metabolites
should help better understand aging pathways and networks and with
—more discoveries in the future— eventually help enhance healthy
aging and longevity.