**4. Summary**

length of life, the number of patients is expected to grow in the coming decades. Other types of brain tumors common in the elderly are primary CNS lymphomas (PCNSLs) and menin-

GBM comprise a rather heterogenic group of neoplasms, with two major types: primary glioblastomas (85–90%) and secondary GBMs that arise from low-grade astrocytomas (10–15%) [175]. Although both types are indistinguishable under the microscope, they appear to differ genetically. Genetically, primary GBMs exhibit by amplification and mutation of the *EGFR* gene, a lack of heterozygosity on chromosome 10q, inactivation of the *PTEN* homolog gene, and only rare occurrence of mutations in the *IDH* and *TP53* genes. Conversely, the genetics of secondary GBM are characterized by mutations in the *IDH* and/or *TP53* genes, as well as platelet-derived growth factor receptor activation [176]. A gene expression-based GBM classification was established by The Cancer Genome Atlas (TCGA) Research Network in 2010. The authors distinguished four subtypes of GBM. Characteristics that differentiate the subtypes at most were indicated as follows: proneural GBM has alterations of the *PDGFRA* gene and point mutations of *IDH1*, classical GBM has *EGFR* aberrations, and mesenchymal demonstrates GBM aberrations in *NF1*. The fourth subtype, neural GBM, is characterized by the expression of neuron markers such as *NEFL, GABRA1, SYT1*, and *SLC12A5*. Each subtype of GBM differs in its sensitivity to radiotherapy and chemotherapy, thus determining the genetic type of a surgically removed or biopsied lesion could protect patients against unnecessary ineffective therapy [177]. Unfortunately, GBMs are mostly incurable in the elderly, with most of these patients surviving less than 6 months [171]. Diagnosis of primary brain tumors in old age can be further complicated and delayed due to nonspecific symptoms that can be masked by physical and cognitive changes observed in the normal aging process [178]. Moreover, elderly patients are an underrepresented group in many clinical trials [179]. The literature data indicate that, at the close of the twentieth century, the chances of receiving a treatment, be that surgery and/ or radiotherapy, were decreasing as the patient got older. Treatment mostly took place for 82% of patients younger than 65 years of age, whereas only 47% of people older than 65 years and merely 25% of patients older than 75 were subjected to any kind of therapy. Additionally, patients treated with radiotherapy and/or surgery had a significantly lower survival rate as

Although pathological processes differ depending on the glioma subtype, there is a common core of molecular events. Growth factor receptor tyrosine kinases cause downstream signaling by activation of extracellular signal-regulated kinases (ERK) or protein kinase B (Akt) pathways. Lack of p53 activation is followed by the loss of the ability to activate DNA repair processes and cell death by apoptosis. An additional adverse characteristic occurring in GBM is that the cells provoke the secretion of vascular endothelial growth factor (VEGF), which is responsible for angiogenesis. The secretion of VEGF by GBM results in vascularization of the tumor, elevation of capillary permeability of the BBB, and creation of extracellular edema

[181]. Finally, due to vasculature growth, there is progression of tumor invasion [182].

Although these brain tumors are very invasive, it is important to note that, depending on the tumor subtype, they may be effectively treated in elderly patients by maximally safe surgical resection, radiotherapy, and/or chemotherapy with Temozolomide, a drug which is especially

giomas [174].

76 Senescence - Physiology or Pathology

they crossed the age border of 60 years [180].

The molecular mechanism of aging includes genome-wide changes such as genomic instability due to accumulation of mutations, telomere attrition, and epigenetic alterations. These changes collect over the years during the life of the organism, leading gradually to morphological and functional deterioration. The brain seems to be particularly vulnerable, as neurons generally do not divide and their pool decreases with the passage of time. Structural changes in the senescent brain affect mostly the cerebral WM and GM; these effects include progressive neuronal loss, decreased levels of neurotransmitters, increased inflammatory processes, and disrupted integrity of vessels and the BBB followed by infarction and microbleeds. These changes may lead to degenerative diseases, such as PD and dementias.

The frequently observed malnutrition and malabsorption syndrome in the elderly may cause decreased concentrations of the vitamins necessary for Hcy metabolism. This in turn results in increased injury to the cerebral vasculature, leading to degeneration and strokes. Consequently, progressive age-related vascular damage of the brain develops, additionally connected to an increased prevalence of epilepsy in the elderly.

An increased incidence of brain tumors may also be observed in old age, probably as an effect of the diminished efficiency of repair mechanisms. The inactivation of genes involved in DNA repair has been shown to advance with age. Such alterations, inflicted either by epigenetic changes or mutation, may cause further destabilization of immunologic systems and cellular repair mechanisms, thus increasing the susceptibility to ROS and spontaneous mutagenesis and resulting in uncontrolled cellular growth and age-related neoplasia (**Figure 2**).



**Figure 2.** Changes during the senescence process may be associated with neurological diseases. The pathological changes starting at the molecular level affect cells of the aging organism and lead to systemic deterioration, giving rise to age-related neurological diseases. ROS—reactive oxygen species, WM—white matter of the brain, and GM—gray matter of the brain.

In summary, the senescence mechanisms start at a molecular level and gradually lead to morphological disintegration and functional loss of brain cells. Finally, they lead to the deterioration of the CNS and an increased risk of developing neurological diseases.
