LMNA, a gene coding for lamins, whose mutations cause many developmental diseases, is linked to Hutchinson-Gilford Progeria (HGP) [1]. HGP is a disease that causes premature aging and is currently affecting around 390 children. Their average life expectancy is around 13 years, but some affected individuals can live to 20 years.
Nuclear lamins are fibrous proteins found in the nuclear envelope, and they contribute to the cellβs structure and play a key role in the regulation of transcription of DNA to RNA. They form the nuclear lamina in the interior of the nuclear envelope with inner nuclear membrane proteins.
Researchers have speculated that lamins have a link to aging [2], as LMNA mutation causes premature aging. Currently, there is evidence for a link between lamins and senescence, epigenetics, and genomic instability. There is not much current research being done in this area, but what we do know is very interesting.
A link between lamins and senescence
Cellular senescence, discovered in 1961 by Leonard Hayflick and Paul Moorhead, is a state in which cells no longer perform their functions, instead emitting a collection of harmful chemicals, known as the senescence-associated secretory phenotype (SASP), that turn other cells senescent. Senescence is primarily caused by telomere shortening and DNA damage, and senescent cells are known to contribute to multiple diseases, such as Alzheimer’s, Parkinson’s, and dementia.
In a study conducted by the Campisi Lab at the Buck Institute for Research on Aging, the nuclei of senescent cells were examined for lamin content [3]. It was found that cells undergoing senescence lacked lamin B1, a critical scaffold of the nucleus and a useful biomarker of aging.
The cells were induced to senesce via DNA damage, replicative exhaustion, and expression of oncogenes, cancer-associated genes. It was found that the activation of several tumor-suppressing pathways associated with senescence, including p53 and pRB, were enough to induce this loss of lamin B1.
However, any of the other positive regulators for senescence, such as the p38 mitogen-activated protein kinase, nuclear factor-ΞΊB, ataxia telangiectasiaβmutated kinase, or reactive oxygen species signaling pathways, did not create this effect, suggesting a link between lamins and cancer.
Lamins and genomic instability
Genomic instability is characterized by a high frequency of mutations in cells during division, and it has been linked to both cancer and aging. Additionally, it is found to be linked to replicative senescence and can potentially induce it in somatic cells.
In a study conducted by researchers in the University of Toronto Cell and Systems Biology Department [4], it was found that the lack of a proteinase responsible for the development of lamin A increased genomic instability, such as DNA damage, and it caused chromosomal aberrations.
This lack of a proteinase also impaired the p53 binding protein 1, which repairs DNA damage, resulting in a slower and less effective response along with more DNA damage.
Lamins and epigenetic changes
Lamin loss is correlated with epigenetic changes and damage over time. In one study, researchers found that nuclear membranes became misshapen over time, causing harmful epigenetic changes. It was found that the overwhelming cause was the gradual loss of lamins.
Right now, researchers are trying to deliver new lamins to cells to increase their overall lifespan and to keep the nuclear membranes in shape.
Conclusion
There is ample evidence for the involvement of lamins in aging and cancer; however, research and demographic studies still need to be conducted to confirm a significant link, as we have only reached the tip of the iceberg. Many labs working on specific topics within aging are linking their topics to lamins, and substantial progress is being made.
Literature
[1] Sinha, J. K., Ghosh, S., & Raghunath, M. (2012). Progeria: A rare genetic premature ageing disorder. Indian Journal of Medical Research.
[2] Rodriguez, S., & Eriksson, M. (2010). Evidence for the Involvement of Lamins in Aging. Current Aging Science, 3(2), 81β89. doi: 10.2174/1874609811003020081
[3] Freund, A., Laberge, R.-M., Demaria, M., & Campisi, J. (2012). Lamin B1 loss is a senescence-associated biomarker. Molecular Biology of the Cell, 23(11), 2066β2075. doi: 10.1091/mbc.e11-10-0884
[4] Liu, B., Wang, J., Chan, K. M., Tjia, W. M., Deng, W., Guan, X., β¦ Zhou, Z. (2005). Genomic instability in laminopathy-based premature aging. Nature Medicine, 11(7), 780β785. doi:10.1038/nm1266
[5] Whitton, H., Singh, L. N., Patrick, M. A., Price, A. J., Osorio, F. G., LΓ³pezβOtΓn, C., & Bochkis, I. M. (2018). Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver. Aging cell, e12742.
