Abstract

Aging is an irreversible biological process observed in living organisms, with each cell demonstrating this mechanism. Age-related decline in cellular integrity due to various endogenous and exogenous factors and mechanisms contributes to several diseases based on the site or location of the decline. Cardiovascular diseases, diabetes, cancer, osteoarthritis, and osteoporosis are some examples of age-related diseases. Reports suggest several premature aging genes contribute to the genetic, pathological, and physiological variations of an organism that is similar to the aging organism and might explain the genes associated with aging. We used the DisGeNET web tool to retrieve genes associated with premature aging. We used the Cytoscape software and STRING online tool for identifying protein-protein networks. We retrieved 136 genes associated with premature aging and compared their association with age-related diseases. Many of these premature agingassociated genes were associated with cardiovascular disease (56), diabetes type II (71), Parkinson's disease (54), Alzheimer's disease (86), prostate cancer progression (23), osteoarthritis (15), osteoporosis (53), age-related macular degeneration (35), cataracts (44), and sensorineural hearing loss (26). This article provides a brief review of some of the genes involved in premature aging.

Keywords: Ageing Ageing associated genes Premature ageing Premature ageing associated genes


Introduction

Aging is a chronological process that is caused by damage to biomolecules, such as DNA, RNA, proteins, and cellular organelles. This damage leads to changes in the functions of cellular organelles, such as the mitochondria, lysosomes, and endoplasmic reticulum. This results in a variety of multicellular functions and age-related diseases that result in death1, 2, 3, 4. This damage is primarily caused by oxidative DNA stress, which results in single-stranded breaks, double-stranded breaks, and modifications to nitrogen bases or sugar-phosphate backbones5, 6. Mitochondria are the powerhouse of the cell and generate energy via the electron transport chain (ETC), which releases free radicals, such as O2- and H+, into the inner mitochondrial membrane space and outer mitochondrial space. These radicals damage cellular DNA, RNA, proteins, and mtDNA, thereby damaging the mitochondria, which results in decreased cellular energy production7. Lysosomes protect cells by degrading damaged or misfolded proteins and malfunctioning cytoplasmic macromolecules via autophagy. Mutations of lysosomal proteins and enzymes lead to lysosomal malfunctioning, which causes excessive amounts of damaged biomolecules to accumulate inside a cell, causing cell damage8. Modifications in rRNA and r-proteins due to oxidative stress leads to ribosomal dysfunction, meaning newly translated proteins may not be able to effectively perform their activities in the cell9.

The past five decades of research indicate that chronic damage or genetic mutations in some of the genes involved in the aging process leads to physiological and pathological changes that are similar to those seen in the aging process10. Bioinformatic tools provide advantages in retrieving enormous amounts of data, while network biology tools can identify associations between genes and proteins. Gene silencing plays a role in inhibiting colon cancer11. In this mini-review, we identified 136 genes associated with premature aging using DisGeNET12, a disease-gene association finding tool, and identified which genes were also associated with other age-related diseases, such as cardiovascular disease, osteoporosis, osteoarthritis, and cataracts. Here, we have briefly reviewed several genes associated with premature aging.

Methodology

We used the DisGeNET12 database for finding genes associated with premature aging and age-related diseases and the STRING database13 and Cytoscape software14 for identifying protein-protein interactions for the genes associated with premature aging. The similarity search was done manually, and relevant articles related to the genes were found using the Google Scholar, Scopus, and PubMed databases.

Aging genes and similarities

We identified 136 premature aging genes (premature aging syndrome; CUI: C0231341) using DisGeNET. Those with the highest scores were Klotho (KL), Werner syndrome gene (WRN), excision repair cross complementation group 6 (ERCC6), amyloid-beta precursor protein (APP), exostosin glycosyltransferase 1 (EXT1), lamin A (LMNA), RecQ like helicase 3 (RECQL3/BLM), RecQ like helicase 4 (RECQL4), tumor protein p53 (TP53), and Sirtuin 1 (SIRT1). When we manually compared the premature aging-associated genes with those associated with age-related diseases, we found several commonalities: 56 of the 1756 cardiovascular disease-associated genes (Cardiovascular Diseases; CUI: C0007222), 71 of the 3134 diabetes type II-associated genes (Diabetes Mellitus, Non-Insulin-Dependent; CUI: C0011860), 54 of the 2078 Parkinson’s disease-associated genes (Parkinson Disease; CUI: C0030567), 86 of the 3397 Alzheimer’s disease-associated genes (Alzheimer’s Disease; CUI: C0002395), 0 of the 166 colorectal cancer-associated genes (Susceptibility to Colorectal Cancer, 12; CUI: C3554460), 23 of the 398 prostate cancer-associated genes (Prostate Cancer Progression; CUI: C1739135), 15 of the 368 osteoarthritis-associated genes (Osteoarthritis, Knee; CUI: C0409959), 53 of the 1098 osteoporosis-associated genes (Osteoporosis; CUI: C0029456), 44 of the 878 cataract-associated genes (Cataract; CUI: C0086543), 35 of the 685 macular degeneration-associated genes (Age-related Macular Degeneration; CUI: C0242383), 26 of the 783 hearing loss-associated genes (Sensorineural Hearing Loss [disorder]; CUI: C0018784)12. As colorectal cancer was not associated with any premature aging genes, it has been excluded from Table 1 (Table 1, Figure 1).

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Figure 1 . Indication of the number of similar genes with premature ageing genes . Various colours indicate various diseases and the number in a square box inside the circle indicates the total number of genes associated with the specific disease and the number inside the white circle indicates the number of similar genes from that specific disease-associated genes.

Table 1.

Genes associated with premature ageing and the number of similar genes associated with various age-related diseases

S/No PMA CVD Diabetes -type II PD AD PPC OA OP ARMD Cataract SNHL No. of age-related diseases the genes are present
1. KL ✓ ✓ ✓ ✓ ✓ ✓ 6
2. WRN ✓ ✓ ✓ ✓ 4
3. ERCC6 ✓ ✓ ✓ ✓ 4
4. APP ✓ ✓ ✓ ✓ ✓ 5
5. EXT1 ✓ ✓ 2
6. LMNA ✓ ✓ ✓ ✓ ✓ ✓ ✓ 7
7. BLM ✓ ✓ ✓ 3
8. RECQL4 ✓ ✓ 2
9. TP53 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 9
10. SIRT1 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 8
11. ZMPSTE24 ✓ ✓ ✓ 3
12. CISD2 ✓ ✓ ✓ 3
13. ATM ✓ ✓ ✓ ✓ ✓ ✓ ✓ 7
14. FGF23 ✓ ✓ ✓ ✓ ✓ 5
15. HTRA2 ✓ ✓ ✓ 3
16. HSPA9 ✓ ✓ ✓ 3
17. SPRTN 0
18. ARNTL ✓ ✓ ✓ ✓ 4
19. CDKN2A ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 8
20. IGF1 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 10
21. CSH1 0
22. CSH2 0
23. SOX2 ✓ ✓ ✓ ✓ ✓ ✓ 6
24. ROBO3 ✓ 1
25. SOD1 ✓ ✓ ✓ ✓ ✓ ✓ ✓ 7
26. BUB1B ✓ 1
27. ANGPTL2 ✓ ✓ ✓ ✓ ✓ 5
28. VDR ✓ ✓ ✓ ✓ ✓ ✓ ✓ 7
29. BMI1 ✓ ✓ ✓ ✓ 4
30. TH tyrosine hydroxylase ✓ ✓ ✓ ✓ 4
31. ELN ✓ ✓ ✓ ✓ ✓ ✓ ✓ 7
32. ERCC8 ✓ ✓ 2
33. CYP27A1 ✓ ✓ ✓ ✓ ✓ ✓ 6
34. DKC1 ✓ ✓ 2
35. EMD 0
36. CDKN1A ✓ ✓ ✓ ✓ 4
37. ERCC2 ✓ ✓ ✓ 3
38. PYCR1 ✓ 1
39. SFRP1 ✓ ✓ ✓ ✓ 4
40. CHMP1B 0
41. WRNIP1 0
42. SOD2 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 8
43. SOD3 ✓ ✓ ✓ ✓ ✓ ✓ 6
44. TWNK ✓ ✓ ✓ ✓ 4
45. SNAI2 ✓ 1
46. PSMD2 ✓ ✓ 2
47. TNMD ✓ ✓ ✓ ✓ ✓ 5
48. RAD51 ✓ ✓ ✓ 3
49. RBBP4 0
50. BCL2 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 8
51. SMURF2 ✓ 1
52. SCT ✓ 1
53. SLC3A2 0
54. SRSF5 ✓ ✓ 2
55. BRCA1 ✓ ✓ ✓ ✓ ✓ ✓ 6
56. CAT ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 8
57. IKBKG ✓ 1
58. CAV1 ✓ ✓ ✓ ✓ ✓ ✓ ✓ 7
59. RUNX2 ✓ ✓ ✓ ✓ ✓ 5
60. TP63 ✓ ✓ ✓ ✓ 4
61. BANF1 ✓ ✓ 2
62. RECQL5 0
63. ATG5 ✓ ✓ ✓ ✓ 4
64. TBPL1 ✓ ✓ ✓ 3
65. CLOCK ✓ ✓ ✓ ✓ ✓ ✓ 6
66. CUL4A ✓ 1
67. SPNS1 0
68. CASP2 ✓ 1
69. SRF ✓ ✓ 2
70. ROPN1L ✓ 1
71. TERC ✓ ✓ ✓ ✓ ✓ 5
72. TERF2 ✓ ✓ ✓ ✓ 4
73. TFAM ✓ ✓ ✓ 3
74. TOP3A ✓ 1
75. C3 complement C3 ✓ ✓ ✓ ✓ 4
76. VCP ✓ ✓ ✓ 3
77. XPO1 0
78. EDS8 0
79. NCOR2 ✓ 1
80. MAPK1 ✓ ✓ ✓ ✓ ✓ ✓ ✓ 7
81. CFDP1 ✓ ✓ 2
82. EFEMP1 ✓ ✓ 2
83. FGF1 ✓ ✓ ✓ 3
84. SIRT2 ✓ ✓ ✓ ✓ ✓ 5
85. FOXO3 ✓ ✓ ✓ ✓ ✓ ✓ 6
86. EXOSC2 ✓ 1
87. COMMD3-BMI1 ✓ ✓ 2
88. KCNH4 ✓ 1
89. FUS ✓ ✓ 2
90. G6PD ✓ ✓ ✓ ✓ ✓ ✓ 6
91. ASPM ✓ ✓ 2
92. IS1 ✓ 1
93. COPD ✓ ✓ ✓ ✓ 4
94. ERCC4 ✓ ✓ 2
95. ERCC3 ✓ ✓ ✓ ✓ 4
96. PPARGC1A ✓ ✓ ✓ ✓ ✓ ✓ ✓ 7
97. TUSC2 ✓ 1
98. H3P10 ✓ 1
99. ADCYAP1 ✓ ✓ ✓ ✓ ✓ 5
100. KCNH8 ✓ 1
101. CYLD ✓ ✓ ✓ 3
102. DPP4 ✓ ✓ ✓ ✓ ✓ 5
103. AGTR2 ✓ ✓ ✓ 3
104. EIF4G2 ✓ ✓ ✓ 3
105. TMEM201 ✓