The practice of calorie restriction is shown to slow the progression of aging and extend healthy life in most species and lineages tested to date, including non-human primates. In humans the degree of life extension is a question mark, as the available data is exceedingly sparse, but the short-term changes are both very beneficial and very similar to those seen in other mammals. Given this, it should be unsurprising to find that calorie restriction slows any one particular aspect of aging, as is the case here for amyloid accumulation in tissues, one of the root causes of age-related disease and dysfunction in normal individuals, but also a prominent feature in a number of genetic diseases. As is frequently true of studies of calorie restriction, the sweeping changes created in the operation of metabolism make it very challenging to determine root causes and chains of cause and effect for the benefits produced, even when those benefits are clear, evident, and robustly reproducible.
Amyloidosis is a group of diseases characterized by extracellular or intracellular deposition of insoluble amyloid fibrils. Fibrils are formed when normally soluble proteins aggregate due to conformational changes caused by various mechanisms. Amyloid fibrils and oligomers of aggregates cause profound dysfunction in both cells and tissues, and these lead to a number of diseases. Apolipoprotein (Apo) A-II is the second most abundant apolipoprotein in serum high-density lipoprotein (HDL) in humans and mice. We found that ApoA-II accumulates to form amyloid fibrils (AApoAII) that deposit extracellularly in various organs with aging. In humans, it is due to a mutation in the normal stop codon in the ApoA-II gene and it has been observed mainly in the kidneys. In aged mice of many strains, it has been observed systemically in several organs. ApoA-II amino acid sequences of humans and mice differ by approximately 40% and they exist in different forms. However, both ApoA-II proteins exist mainly in HDL particles and they may have similar roles.
We have reported that administration of a very small amount of AApoAII fibrils markedly accelerated amyloid deposits in young mice. Intriguingly, our recent studies have suggested that AApoAII amyloidosis was transmissible by a prion-like infectious process through a seeding-nucleation mechanism. These findings have suggested that mouse AApoAII amyloidosis is an extremely useful model for the analysis of systemic amyloidoses and the development of new preventive treatments for amyloidoses. Nutritional control and caloric restriction (CR) may be the most readily available treatment to prevent or slow these amyloidoses. In particular, CR, i.e., a ~60% reduction of intake compared to an ad libitum (AL) diet, has been reported to be the most effective non-genetic treatment to decelerate aging and extend life- and health-span.
The molecular mechanisms by which longevity is promoted by CR intervention are complex. One important metabolic reaction mediated by CR is autophagy. This process supplies organisms with nutrients via the cytoplasmic recycling system. It also maintains damaged organelles and proteins during aging and increases longevity. The underlying mechanisms by which CR treatment mitigates Alzheimer's disease are suggested by a number of observations. First, both circulating insulin and insulin signaling are altered by CR treatment, enhancing the degradation of amyloid-β via enzymatic processes. Second, CR treatment activates sirtuin-1 (SIRT1) signaling and enhances the function of non-amyloidogenic processing enzyme of the amyloid precursor protein. Third, autophagy induced by CR treatment appears to suppress the progression of Alzheimer's disease. In this regard, there are two reports that demonstrated that activated autophagy degraded amyloid fibrils or reduced levels of amyloid-β peptide and amyloid precursor protein.
In AApoAII amyloidosis, we previously reported that chronic CR (60% caloric intake compared with an AL group) decelerated the advancement of senescence in SAMP1 mice and inhibited the spontaneous deposition of AApoAII fibrils with aging. However, the mechanisms reducing amyloidosis were unclear. Here, we hypothesize that CR treatment does indeed play a preventive role against the progression of systemic amyloidosis. Moreover, we demonstrate that CR treatment reduced the progression of amyloidosis in mice with inducible systemic AApoAII amyloidosis. We suggest that suppressing the levels of amyloid precursor proteins in the body might be a good first step in preventing amyloid deposition in almost all amyloidoses. From our data, CR treatment might lessen amyloid deposition by reducing oxidative stress and improving the unfolded protein response. These results suggested that the beneficial effects of CR are indeed complex. It is currently difficult to pinpoint the direct effects of CR that suppress amyloid deposition.