Table 1.

Types of GIN and their association with aging, CIN and neurodegeneration.

Type of GIN	Association with aging	Association with CIN	Association with ND
DNA mutations	Mutations accumulate with age, likely through reduction in efficiency of NER, BERand NHEJ repair pathways (Coppede and Migliore, 2010; Maslov and Vijg, 2009; Maynard et al., 2015). Age-related accumulation of DNA oxidation occurs in vitro and in vivo. Mutations in the NER pathway lead to premature aging disorders XP and CS (Cooke et al., 2003; Coppede and Migliore, 2010; Maynard et al., 2015).	Prolonged mitotic arrest generates γ-H2AX foci (Ganem and Pellman, 2012; Hayashi and Karlseder, 2013). Aneuploidy triggers unbalanced levels of proteins for genome maintenance (Holland and Cleveland, 2012b; Meena et al., 2015; Nicholson and Cimini, 2015). Cleavage furrow damage (Ganem and Pellman, 2012; Janssen et al., 2011).	In vivo models of ND show DNA damage (mainly oxidative) as a common precursor of motor neuron death (Martin, 2008; Uttara et al., 2009). Mutations in genes involved in DNA repair or DNA-damage response are associated with neurodegenerative diseases, including XP, CS, TTD and AT (Coppede and Migliore, 2010; Martin, 2008). Increased DNA and RNA oxidation occurs in AD and PD brains, and high DNA oxidation in found in ALS samples (Coppede and Migliore, 2015).
mtDNA damage	mtDNA alterations accumulate during aging in some tissues. Deletions are associated with respiratory chain defects and they increase with age in the CNS (Reeve et al., 2008). mtDNA mutagenesis alone can cause degenerative age-related symptoms (Greaves et al., 2012). mtDNA mutations are associated with nuclear signaling pathways and influences the process of aging (Cha et al., 2015).	Aneuploid cells have increased levels of mtDNA (Fragouli et al., 2015). Dysfunctional mitochondria have been associated with higher chromosome segregation errors (Coskun and Busciglio, 2012).	High levels of mtDNA deletions in neurons have been found in ND (Reeve et al., 2008). Mitochondrial dysfuntion induced by mtDNA mutations cause degeneration of dopaminergic neurons. Huntingtin-expressing and HD cells have higher levels of mtDNA damage (Cha et al., 2015). mtDNA damage is present in PD (Coppede and Migliore, 2015; Greaves et al., 2012; Reeve et al., 2008), AD (Cha et al., 2015; Coppede and Migliore, 2015), and ALS patients (Coppede and Migliore, 2015).
CNVs	Deletions are associated with mortality at old age (Kuningas et al., 2011; Nygaard et al., 2015). Deletion in Contactin-Associated-Protein-Like 4 negatively correlates with female survival at the age of 80 (Iakoubovet al., 2013). Negative association between CNV in Contactin-Associated-Protein-Like 2 is known healthy aging males (Iakoubovet al., 2015).	CNVs target genes that control the mitotic cell cycle progression (Iourov et al., 2015).	Large deletions are associated with cognitive impairment in AD (Guffanti et al., 2013). CNV of glucose transporter SLC2A3 delays the onset of HD (Vittori et al., 2014). Triplication of the α-Synuclein locus is the cause of autosomal dominat familial PD, and CNVs in the Parkin gene are associated with recessive inheritance of PD (Singleton et al., 2003; Toft and Ross, 2010).
DMs	Limited reports. Increased frequency in murine aged kidney (Martin et al., 1985). No increase observed in in vitro aging of fibroblasts (Reis et al., 1985).	Unclear.	Linked to therapy resistance: high frequency in neuroblastomas (Fan et al., 2011). Myc amplification in medulloblastoma, EGFR and other genes in glioma (Gebhart, 2005). 50% of high-grade astrocytomas and glioblastomas have DMs (Giollant et al., 1996).
Micronuclei	Age-related increase in micronuclei frequency has been associated with loss of sex chromosomes (Bolognesi et al., 1999; Bukvic et al.,2001; Guttenbach et al., 1994; Hando et al., 1994; Nath et al., 1995). Micronuclei are frequent in HGPS cells, premature aging disorders, and incidence increase with age (Bridger and Kill, 2004; Migliore et al., 2011).	Can arise from mitotic spindle dysfunction (lagging chromosomes or from acentric chromosomal fragments) and can cause aneuloidy (Balmus et al., 2015; Cimini, 2008). They function as a mode to eliminate structurally abnormal or supernumerary gene copies (Ambros et al., 1997; Casati et al., 1995).	Peripheral lymphocytes from AD and PD patients and skin fibroblasts from AD and HD patients have increased frequency of micronuclei (Coppede and Migliore, 2015; Migliore et al., 2011). Neuroblastoma cell lines can actively elimininate extra copies of MYCN via micronuclei (Ambros et al., 1997).
Chromotripsis	Not defined association with aging or longevity.	Micronuclei have been proposed as an intermediate step leading to chromothripsis through the defective DNA repair mechanism and replication fork collapse present in micronuclei (Crastaet al., 2012; Rausch et al., 2012).	Occurs in 18% of high-stage neuroblastoma (Molenaaret al., 2012). Associated with gene amplification of receptor tyrosine kinases and modulators o TP53 and RB1 pathways in glioblastoma (Furgason et al., 2015).
Dysfunctional telomeres	Most human tissues but the bain, show significant telomere shortening during aging. Some age-related diseases are associated with telomere shortening (Jiang et al., 2007). DC patients carry mutation in telomerase (TERT and TERC) and present accelerated aging (Sahin and Depinho, 2010). Centenarians and their offspring maintain longer telomeres (Atzmon et al., 2010).	Bridge chromatids resulting from telomere fusion may be involved in missegregation events resulring in aneuploidy (Pampalona et al., 2010a). Aneuploidy may confer the ability to survive telomerase insufficiency (Millet et al., 2015).	No consistent relationship between telomere length and AD or PD but their shortening is associated with dementia and cognitive decline (Eitan et al., 2014). Short telomeres due to accelerated erosion have been reported in FA patients' leukocytes, and cerebellar tissues (Anjomani Virmouni et al., 2015). Telomerase reactivation reverses neurodegeneration phenotypes in aged telomerase-deficient mice (Jaskelioff et al., 2011).
Abnormal nuclear architecture	Premature aging disorders like HGPS are caused by mutations in LMNA or pre-lamins. Progerin, a truncated form of A-type lamin, accumulates with age (Gonzalo, 2014; Kudlow et al., 2007; Worman et al., 2009).	In vitro downregulation of lamin A/C cause aneuploidy (Capo-chichi et al., 2011a,b).	Accumulation of Huntingtin aggregates causes focal distortion of the nuclear envelope (Chapple et al., 2008). PD-associated mutation in LAMNA leads to abnormal nuclear architecture (Liu et al., 2012). Disruption of lamin A/C normal architecture is found in the nucleus in FXTAS (Arocena et al., 2005).