Table 1.

Summary of senescent phenotypes in normal aging, Alzheimer’s disease (AD), Down syndrome (DS), Parkinson Disease (PD).

Senescence phenotypes	Normal aging	AD	DS	PD
Cell cycle arrest	Cell cycle arrest (alterations in cell and tissue functions).	Cell cycle prolongation and re-entry.	Cell cycle arrest and elongation.	Cell cycle arrest (alterations in the expression of several genes implicated in the cell cycle).
SASP	Brain mild chronic inflammation, changes in microglia morphology, altered microglia activation, enhanced release of proinflammatory mediators.	Microglia overactivation, enhanced release of proinflammatory cytokines and other SASP that aggravate amyloid and tau pathology.	Microglia overactivation, proinflammatory mediators’ over-expression, increased release of proinflammatory cytokines from early late stages, as the person ages this is enhanced and aggravates AD neuropathology.	Activation of microglia and pro-inflammatory mediators release that has a role in the dopaminergic loss.
Oxidative stress and mitochondrial dysfunction	Increased ROS and mtROS. Altered mitochondrial integrity and function that compromises cell metabolism (reduces ATP) and induces damage DNA.	Increased ROS and altered mitochondrial structure and function that produces cellular changes associated with senescence.	Increased ROS and mtROS from embryonic stages. Altered mitochondrial structure and function that compromises cell metabolism (reduces ATP production). As the person ages, oxidative stress is enhanced and aggravates AD neuropathology. Oxidative stress-induced damage of DNA, lipids, and proteins.	Increased ROS and mtROS. Altered mitochondrial structure and function. Mutation of genes associated with pathways of mitochondrial dysfunction.
Telomeric DNA damage	Telomere attrition (replicative senescence) and damage.	Telomeric DNA damage. Regarding telomere shortening: controversial results.	Shorter telomeres correlate with the degree of dementia in DS individuals with AD.	Contradictory results regarding telomere length.
Non-telomeric DNA damage and DNA repair mechanism	Increased DNA damage accumulation and alteration in DDR.	Increased DNA damage and alterations in DDR.	Oxidative stress and other stressors enhance DNA damage accumulation. Overexpression of the USP16 gene and the reduced DNA POLb alter DNA repair mechanisms and chromatin remodeling. Genomic instability.	Genetic instability due to gene mutations, altered gene expression or regulation leading to cell cycle alterations. Impaired DNA repair mechanisms that increase the duration of cell cycle.
Epigenetic modifications	Alterations in histones, DNA methylation pattern, chromatin architecture, and micro RNAs expression.	Aberrant phosphorylation of histones, changes in DNA methylation of AD critical genes. Mislocated chromatin organizing proteins and epigenetic regulators.	Histone modifications, DNA hypermethylation, alteration in small non-coding RNAs implicated in premature aging and cognitive defects.	Changes in DNA methylation, posttranscriptional modification of histones.
Morphological changes	Increased size, flat and irregular shape, changes in membrane composition.	Increased size, flat and irregular shape, changes in membrane composition.	Increased size, flat and irregular shape, changes in membrane composition.	Increased size, flat and irregular shape, changes in membrane composition.
Altered proteostasis	Nucleolar dysfunction, altered transcription, endoplasmic reticulum stress, proteasome and autophagy anomalies.	Loss of protein homeostasis. Nucleolar dysfunction. Accumulation of abnormal proteins (amyloid peptides and hyperphosphorylated tau).	Increased gene copy number alters proteostasis. Alterations in the ribosome biogenesis machinery (increases number of nuclear organizer regions resulting in excessive rRNA and ribosomal protein synthesis leading to waste energy. Alterations in the protein degradative systems (autophagy and proteasome). Altered proteostasis leads to increases in amyloid aggregates and tau hyperphosphorylation.	Accumulation of misfolded proteins. Accumulation of neurotoxic α-synuclein associated with Lewy bodies. Autophagic/lysosomal dysfunction.
Others	Accumulation of lipofuscin		Early aging, and development of senescence phenotype in the brain and other tissues.