**2. Biological aging: Is it a major risk or the basic causative factor for neurodegeneration?**

Age is the main factor in major debilitating and life-threatening conditions, including cancer, cardiovascular disease, diabetes, and neurodegeneration, all of which are therefore increasing in prevalence [2]. Nowadays almost all can make it to the old and nobody can say anymore that reaching old age is a fortune, and between those who should solve social and health problems of older people prevails the old slogan "old age is not a disease." For many scholars, however, modern scientific discoveries confirm the deductions of ancient philosophers: all living beings, without exception, would be affected by an innate chronic degenerative disease, we call it aging, characterized by having an incubation period as long as be compatible with the reproductive success of the species. If aging is a disease and not a simple disability and disease risk factor, it is not surprising that the diseases associated with it (cancer, neurodegeneration, atherosclerosis, diabetes, etc.) can be regarded as signs or easily preventable complications, all together, by fighting the underlying disease. The prescription is simple but hard to follow a sober physically active lifestyle; to eat fruits, vegetables, fish, and little red meat; to take food after having been hungry for a few hours; to take supplements rich in polyunsaturated fatty acids (PUFAs) after dinner regularly; and to make good use of all functions of all organs of our body, including brain. This is exactly what cardiologists, diabetologists, oncologists, and neurologists all recommend for primary prevention. Understanding exactly the causes of aging and of all ageassociated diseases may help to tackle the growing problem of neurodegeneration. Free radicals are the root of all evil. They may be generated either by endogenous (metabolic) causes or by environmental factors, including pollution (living less than 50 m from a major traffic road may increase hazards ratio of incident dementia by a 10% [3] and even oral hygiene and chronic inflammation [4]). Perhaps, we should remind here the oxygen paradox: without oxygen we die in minutes; with oxygen we grow old and die [5]. Oxygen is actually slowly poisonous, and it just takes 75–100 years to kill us, difference depending on how much we use and how we deal with it and repair the endogenous oxidative damage to protein, lipids, and (most important) DNA responsible for intrinsic aging, as well as the additional free radical-mediated damage from the inflammatory responses and environmental factors (e.g., ionizing radiation) [6]. It was computed that the oxygen consumption of human brain may be higher than 3 mL (i.e., about 1020 oxygen molecules)/g/min. In humans, over 99% of these molecules do generate water safely, but 1018 per min will produce free radicals, approximately 106 free radicals per cell per min. It was estimated that the number of oxidative hits to DNA in the human cell per day is about 10,000 and that DNA-repair enzymes efficiently remove 99.9% of the lesions formed so that only one oxidative lesion accumulate in the DNA of any cell every day. This is not nothing: it makes over 30,000 lesions in a long life [7]. Since there are about 20,000 genes in human cells, by the age of 100 years, all neurons may carry about two mutations a gene on the average. Why be surprised if over time cell functions are reduced?

**21**

**Table 1.**

*Primary Prevention of Alzheimer's Disease (AD) DOI: http://dx.doi.org/10.5772/intechopen.85418*

With AD patients, the brain is smaller than normal and of reduced weight. A reduction of the thickness of the convolutions is evident. Atrophy is more evident in the temporal lobe, particularly in the parahippocampus, but also in the frontal and parietal regions. The occipital lobe and the motor cortex may be spared. Histologically, several major changes are recognized in AD. Amyloid, consisting of accumulations of Aβ peptide, is deposed in the cerebral cortex in the form of spherical deposits called senile plaques. Intraneuronal inclusions are formed in the cortical neurons, constituted by abnormal, often flame-shaped, bundles of filaments called neurofibrillary tangles, which occupy a large part of the neuronal cytoplasm, and are made up of a protein that binds to the microtubules, called tau protein. The processes of the cortical nerve cells diverge, twist, and dilate due to the accumulation of filaments in the form of tangles [8]. Changes are due to oxidative stress damage and to the relative failure of repair mechanisms at the molecular and subcellular (autophagy) level and result in the disruption of the neural network (**Table 1**). It is customary to distinguish two forms of AD. There is indeed a precocious rare form that occurs between 30 and 60 years, with a peak in the fifties, with a formation of the amyloidogenic peptide Aβ (1-42) from APP genetically favored by particular isoforms of presenilin 1 and 2 or of APP. The other form, sporadic, more frequent, late-onset (observed after age 65 with a frequency that increases with age) is due to the progressive increase in oxidative stress and decline with increasing age in mitochondrial and peroxisomal maintenance and in the efficiency of the mechanisms that neutralize free radicals and repair damage. This latter form might be postponed successfully to time of death by anti-aging interven-

tions (nutrition, physical activity, damage repair, nerve growth factors).

**Mechanism of repair Effects of the age-related decline**

Autophagy and lysosomal function Accumulation of altered mitochondria

*and physical activity depend at least in part from the induction of repair mechanisms.*

*Effects of failure of repair mechanisms at the molecular, subcellular, and cellular level.*

**4. The primary cause of AD and the roles of cholesterol and unsaturated** 

It is obvious that native APP cannot be the ultimate substrate for γ-secretase trimming. Hence, both with the earlier and the later form of AD, the rate of Aβ

Apoptosis Accumulation of damaged, misfunctional cells in all tissues *There is evidence that the above-mentioned repair mechanisms are responsible for cleaning cells from any produced waste and for getting tissues rid of irreversibly altered cells. In younger persons, functions are redundant but progressively decline with increasing age, and may gradually fail in older persons resulting in the accumulation of "waste" in cells and tissues. On a healthy life, "waste" is the limiting factor for cell and tissue "cleaning" activities, but waste recognition-acuity co-varies with cell and body request for nutrients and repair. Function of all repair mechanisms are inducible (or suppressible) depending on life style. Benefits from healthy life style, diet restriction,* 

Accumulation of DNA lesion Accumulation of altered proteins Changes in polyunsaturated fatty acids

Accumulation of protein aggregates Changes in membrane proteins and lipids

**3. Pathology of AD**

**fatty acids**

Molecular level DNA repair Proteasome Phospholipid repair

Subcellular Level

Cellular and tissue level
