Telomere Biology, Erosion, and Age-Related Conditions: Insights from Down Syndrome and Other Telomere-Associated Disorders

Abstract

Telomeres play a crucial role in safeguarding DNA integrity. With each cell division, these protective structures undergo shortening, limiting the number of divisions to prevent improper genetic material distribution in aging cells. Senescent cells accumulate in tissues and contribute to age-related changes and decreased regeneration. Various genetic conditions are linked to premature aging and the early onset of age-related disorders. Down syndrome (DS), or chromosome 21 trisomy, is a relatively frequent aneuploidy, having an incidence of 1/1000-1/1100 newborns, and a major cause of intellectual disability. DS individuals exhibit a higher prevalence and earlier onset of age-related disorders, particularly Alzheimer's disease, due to the buildup of beta-amyloid. In DS individuals, telomere erosion occurs at an accelerated rate, caused by the overexpression of numerous genes, and it is associated with various factors, including obesity, inflammation, hormonal fluctuations, physical or emotional stress, higher levels of reactive oxygen species, and autoimmune disorders. Although telomere length in DS children is initially higher than in the general population, their telomeres experience a more rapid shortening process. Developing strategies that target molecular pathways linked to telomere erosion and telomerase activity could become a key point for the therapeutic management of DS individuals.

Keywords: Age-related disorders; Down syndrome; Premature aging; Telomerase activity; Telomere length.

Fig. 1

Telomere components with the 6 subunits of the shelterin complex (corresponding to TRF1, TRF2, POT1, RAP1, TPP1, and TIN2) [–24]. Comprising the repetitive sequence of six nucleotides (5′-TTAGGG-3′) tandemly repeated over a span of 5–15 kilobases, human telomeres feature a G-rich strand that extends outwardly, forming a protrusion at the chromosome end known as the 3′ G-rich overhang [3, 29]. a The telomeric 3′ G-rich overhangs can fold back and invade the double-stranded telomeric DNA to form a displacement loop (D-loop), which facilitates the formation of the protective T-loops structure, which are akin to lariat-like structures (a structure resembling a lasso) [29, 30]. b Additionally, the 3′ G-rich overhang in telomeres has the capability to create stable intramolecular and intermolecular structures composed of four-stranded non-B DNA, known as G-quadruplex structures

Fig. 2

Telomere shortening process with each cell division; in some specific conditions, such as increased oxidative stress or certain cell types undergoing extensive division, this shortening can be even more pronounced [31, 32] sometimes exceeding 500 bp per cell division [40] (bp = base pairs)

Fig. 3

Factors involved in telomere length determination [, , , , –64]. (GH, growth hormone; T4, thyroxine; T3, triiodothyronine)

Fig. 4

Age-related conditions in Trisomy 21 [, , , –144]