A metabolic signature predicts biological age in mice

Abstract

Our understanding of the mechanisms by which aging is produced is still very limited. Here, we have determined the sera metabolite profile of 117 wild-type mice of different genetic backgrounds ranging from 8 to 129 weeks of age. This has allowed us to define a robust metabolomic signature and a derived metabolomic score that reliably/accurately predicts the age of wild-type mice. In the case of telomerase-deficient mice, which have a shortened lifespan, their metabolomic score predicts older ages than expected. Conversely, in the case of mice that overexpress telomerase, their metabolic score corresponded to younger ages than expected. Importantly, telomerase reactivation late in life by using a TERT-based gene therapy recently described by us significantly reverted the metabolic profile of old mice to that of younger mice, further confirming an anti-aging role for telomerase. Thus, the metabolomic signature associated with natural mouse aging accurately predicts aging produced by telomere shortening, suggesting that natural mouse aging is in part produced by presence of short telomeres. These results indicate that the metabolomic signature is associated with the biological age rather than with the chronological age. This constitutes one of the first aging-associated metabolomic signatures in a mammalian organism.

Figure 1. Age predictions with respect to the wild-type mice metabolomic signature

The wild-type mice metabolomic ageing changes (black diamonds) fits a linear model: Predicted Age =0.934·Actual Age + 3.971 (r²=0.944). A) G1 Terc^−/− samples (red circles); B) K5-Tert samples (blue circles); C) Sp53/Sp16/Sp19Arf/K5-Tert samples (green circles); D) Sp53/Sp16/Sp19Arf samples (purple circles). p-values for Fig. 1 b-d correspond only to mice over 60 months of age.

Figure 2. Metabolite profile plots (mean ± 1 standard error of the mean)

A) Rt = 7.4 min, m/z = 776.5789 (not determined); B) LysoPE(20:3); C) SM(d18:1/16:1); D) PE(P-16:0/22:6); E) PE(16:0/18:2); F) PE(16:0/22:6). WT samples (black); K5-Tert samples (blue); Terc^−/− samples (red).

Figure 3. PCA scores plot discriminating two years old AAV9-GFP from one year old AAV9-GFP and two years old AAV9-mTERT treated mice

Duplicate sample injection data are shown (duplicate sample extracts were injected in each ionization mode as quality controls).

Figure 4. Profile plot of biomarkers

Raw intensity data, including average group intensities, number of samples and p-values, corresponding to the highlighted biomarkers.