*3.3.1. Aging*

The aging process is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication [103]. In particular, the mitochondrial dysfunction leads to higher formation of reactive oxygen species (ROS) and enhanced oxidative damage [104]. Both processes can be diminished by the antioxidant function of vitamin E [105]. Consequently, two questions arise: (i) can vitamin E modulate the aging processes or prevent age-related diseases? This has been subject of several reviews [106–109]. (ii) And how is the concentration, distribution, and function of vitamin E modulated by the aging process? In humans, age-dependent changes of α-TOH plasma concentrations are known. In healthy aged humans, the α-TOH plasma concentrations are higher than in younger individuals [110–113]. However, this might be due to the agerelated increase of plasma cholesterol concentrations, as the age-related increase in α-TOH plasma concentrations disappear after adjustment for cholesterol plasma concentrations [112] or serum lipids [113]. Traber et al. suggested that α-TOH plasma concentrations are more dependent on control mechanisms for plasma lipids rather than on α-TOH absorption [113]. Hospitalized elderly patients [114] as well as older persons with cognitive impairments (dementia or Alzheimer's disease [115, 116]) have low α-TOH plasma concentrations [117]. However, an unfavorable nutrient status of the hospitalized patients was discussed as the cause of the lower α-TOH plasma concentrations.

Several studies analyzed the age-dependent changes of α-TOH tissue concentrations and handling in mice [37, 117–119] and rats [120]. In brain [37, 117, 118] and kidney [37, 117], epididymal adipose tissue [117] and aortic vessel wall [120], a consistent increase in α-TOH was found with age. In old rats, however, an age-dependent increase in intestinal absorption was found [121]. This was considered as a "*self-protective age-dependent adaption"* [120], which is thought to counteract increased oxidative stress during aging. In the liver and heart, however, data are conflicting: while some found increased concentrations [37, 119, 120], Takahashi et al. found decreased values [117]. Two studies also analyzed the age-dependent regulation of genes, known to be involved in vitamin E handling, which are α-TTP, ABCA1, and Cyp4f14 (murine orthologue of CYP4F2) [117] as well as NPC1, NPC2, and LPL [37]. Takahashi et al. found increasing (mice with the age of 3–12 month) and then decreasing (12—24 months) α-TTP protein levels in the liver, while mRNA expression was stable over age [117]. Overall, Cyp4f14 mRNA expression decreased during aging (60% decrease in mRNA expression at the age of 24 months compared to the age of 3 weeks), while ABCA1 mRNA expression slightly increased (20% in the same age range as measured for Cyp4f14) [117]. The authors concluded that the age-related changes of hepatic α-TOH levels cannot be explained by the metabolism of α-TOH via Cyp4f14. König et al. analyzed protein expression in kidney tissue or its lysosomal membranes and found a significant decrease of NPC1 and NPC2, but a prominent increase in LPL (361% compared with the tissue from younger mice) [37]. The increased expression of LPL may explain the accumulation of α-TOH in aged mice. Furthermore, NPC1 and NPC2 may be responsible for the transport of α-TOH from the endosomes to the cytosol [69] and their reduced expression may explain the accumulation of α-TOH in lysosomal membranes [37]. In summary, there are age-dependent changes in α-TOH tissue and plasma concentrations and also in the expression of genes responsible for vitamin E handling; however, the underlying regulatory processes are not unraveled completely yet.
