Sixty years old is the breakpoint of human frontal cortex aging

Abstract

Human brain aging is the physiological process which underlies as cause of cognitive decline in the elderly and the main risk factor for neurodegenerative diseases such as Alzheimer's disease. Human neurons are functional throughout a healthy adult lifespan, yet the mechanisms that maintain function and protect against neurodegenerative processes during aging are unknown. Here we show that protein oxidative and glycoxidative damage significantly increases during human brain aging, with a breakpoint at 60 years old. This trajectory is coincident with a decrease in the content of the mitochondrial respiratory chain complex I-IV. We suggest that the deterioration in oxidative stress homeostasis during aging induces an adaptive response of stress resistance mechanisms based on the sustained expression of REST, and increased or decreased expression of Akt and mTOR, respectively, over the adult lifespan in order to preserve cell neural survival and function.

The role of mitochondrial ROS in the aging brain

“…Surprisingly, not all respiratory complexes are affected equally by aging. The activity of CIV and the activity and levels of CI have been reported by many studies to be reduced, whereas changes in the activity/levels of other respiratory complexes are inconsistent. The reduction in the activity of specific respiratory complexes or the alteration in the ratio between them will have important consequences on ROS levels.…”

“…The brain is particularly sensitive to oxidative damage due to its high rate of oxygen consumption, the abundance of polyunsaturated fatty acids prone to oxidation, and the increased concentration of transition metals such as iron or copper. Due to the heterogeneous nature of the brain which includes several cell and subcell types certain areas of the brain are more sensitive than others to changes in oxidative stress or levels of ROS . It is important to highlight that ROS can cause reversible redox modifications (mainly in proteins, for example, reversible oxidation of specific cysteines) as well as irreversible oxidative damage, that is, causing structural damage in biomolecules.…”

Succination of Protein Thiols in Human Brain Aging

“…MS-based techniques-specifically gas chromatography-MS (GC/MS)-can also be used to detect and measure the steadystate level of 2SC at the subcellular, cellular, tissue, and organ levels (Nagai et al, 2005(Nagai et al, , 2007Alderson et al, 2006;Blatnik et al, 2008a;Frizzell et al, 2009;Cabré, 2015;Gomez et al, 2015;López-González et al, 2015;Cabré et al, 2016Cabré et al, , 2017Martínez-Cisuelo et al, 2016;Piroli et al, 2016;Naudí et al, 2017). In this approach, 2SC can be determined as TFAME (trifluoroacetic acid methyl esters) derivatives in protein samples (around 0.5-1 mg of protein final concentration) previously hydrolyzed in acidic conditions and using a GC coupled to an MS, an HP-5MS column (30 m × 0.25 mm × 0.25 µm), and a specific temperature program ranging from 110 • C to 300 • C. Later, quantification can be made by internal and external standardization using standard curves created from mixtures of deuterated and non-deuterated standards.…”

“…Effectively, the available evidence demonstrates that protein succination occurs in brain tissue as in other cell systems. Thus, the formation of 2SC has been described in several brain regions in mouse (López-González et al, 2015;Piroli et al, 2016), rat (Cabré, 2015) and human (Cabré et al, 2016(Cabré et al, , 2017Naudí et al, 2017). By using immunoblotting, 2SC was detected in several mouse brain areas including olfactory bulb, cortex, striatum, cerebellum, and brainstem (Piroli et al, 2016).…”

“…With this premise, different non-enzymatic PTMs were analyzed in the frontal cortex of healthy humans covering an age range from 40 to 90 years old, using MS (Cabré et al, 2017). The results demonstrated increased protein oxidative (aminoadipic-and glutamic-semialdehyde markers) and lipo-and glycoxidative (carboxyethyl-and carboxymethyllysine markers) damage in human frontal cortex during the healthy adult lifespan, with a breakpoint at 60 years old (Cabré et al, 2017). Remarkably, this accumulation of oxidative damage with age is selective because when compared with the non-enzymatic modification of cysteine residues (2SC and carboxymethyl-cysteine), no changes were observed.…”