Older and Younger Cells Handle Genes Differently

Knocking down genes doesn't always have the same effect.


Cells with shrunken mitochondriaCells with shrunken mitochondria

In Aging Cell, researchers have published evidence that downregulating a key aspect of lipid metabolism harms mitochondrial function, but only in cells taken from younger people.

Fat regulation at the cellular level

Perilipins (PLINs) are proteins that regulate the use of fats (lipids) within cells. This paper focuses on PLIN2, which has previously been investigated in the context of aging [1] and plays a significant role in lipid metabolism [2]. PLIN2 plays a role in diabetes [3] and has been investigated in cancer, although its role varies by the cancer type [4].

Most pertinent to this study, PLIN2 plays a role in the maintenance of mitochondria. Downregulating it in pancreatic beta cells, which produce insulin, has been shown to impair that critical function and harm mitochondria, particularly their ability to metabolize oxygen [5]. On the other hand, it also plays a role in mitochondrially mediated cellular senescence under stress conditions [6], and it increases with age in skeletal muscle and brain cells. These researchers have previously associated it with sarcopenia [7].

To determine its roles in mitochondrial dysfunction and cellular senescence, the researchers tested it on cells taken from older and younger cohorts, and their findings were surprising.


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Same amount, different processing

Six people between the ages of 25 and 34 along with five people between 63 and 78 were recruited for this study. These participants had dermal fibroblasts extracted and cultivated, and then some of the cells were subjected to RNA that silenced most expression of PLIN2, PLIN3, or the related factor GDF15; this silencing did not affect the cells’ viability.

Interestingly, these cells, unlike brain cells, do not have significantly different amounts of PLIN2 or PLIN3 between older and younger people. Instead, the researchers found that fatty acid accumulation causes increased expression of PLIN2.

In fibroblasts that had their PLIN2 expression knocked down, multiple other gene expressions related to lipid handling were affected. However, PLIN3 did not seem to have a similar effect. Knocking down PLIN2 significantly decreased the accumulation of lipids within these cells.

While this may seem beneficial, the researchers were able to confirm previous research demonstrating its negative mitochondrial effects [5], impairing respiration in general. This was only significant in cells taken from younger people; cells from older people trended towards worse respiration, but to a much lesser degree. Analyzing gene expression, the researchers found that younger and older cells had entirely different strategies for dealing with PLIN2 knockdown: the younger cells increased mitochondrial turnover, while the older ones increased mitochondrial fusion.

The role of GDF15

Both older and younger cells expressed markers of mitochondrial stress with PLIN2 knockdown, most notably of GDF15, which older cells expressed more of than younger cells did. GDF15 expression was also found to be associated with an increase in cellular senescence. Further experiments involving knocking down both PLIN2 and GDF15 found that cellular senescence was reduced to the level of cells without any RNA knockdowns at all, demonstrating that it is indeed the cause in this case.


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Differences were also found between younger and older cells when GDF15 was knocked down. Similarly to PLIN2, genes that were significantly downregulated along with GDF15 knockdown in younger people’s cells were not significantly affected in those of older people.

The researchers note that many of their findings are limited and somewhat murky; while the effects of these knockdowns on younger cells are largely clear, the effects on older cells are less so. Further research will have to be conducted to determine what biochemical changes have occurred with age and what might be able to be done about them.

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[1] Conte, M., Franceschi, C., Sandri, M., & Salvioli, S. (2016). Perilipin 2 and age-related metabolic diseases: a new perspective. Trends in Endocrinology & Metabolism, 27(12), 893-903.

[2] Xu, S., Zou, F., Diao, Z., Zhang, S., Deng, Y., Zhu, X., … & Liu, P. (2019). Perilipin 2 and lipid droplets provide reciprocal stabilization. Biophysics Reports, 5, 145-160.

[3] Ji, J., Petropavlovskaia, M., Khatchadourian, A., Patapas, J., Makhlin, J., Rosenberg, L., & Maysinger, D. (2019). Type 2 diabetes is associated with suppression of autophagy and lipid accumulation in β‐cells. Journal of cellular and molecular medicine, 23(4), 2890-2900.


[4] Hayakawa, M., Taylor, J. N., Nakao, R., Mochizuki, K., Sawai, Y., Hashimoto, K., … & Harada, Y. (2023). Lipid droplet accumulation and adipophilin expression in follicular thyroid carcinoma. Biochemical and biophysical research communications, 640, 192-201.

[5] Mishra, A., Liu, S., Promes, J., Harata, M., Sivitz, W., Fink, B., … & Imai, Y. (2021). Perilipin 2 downregulation in β cells impairs insulin secretion under nutritional stress and damages mitochondria. JCI insight, 6(9).

[6] Che, L., Huang, J., Lin, J. X., Xu, C. Y., Wu, X. M., Du, Z. B., … & Lin, Y. C. (2023). Aflatoxin B1 exposure triggers hepatic lipotoxicity via p53 and perilipin 2 interaction-mediated mitochondria-lipid droplet contacts: An in vitro and in vivo assessment. Journal of Hazardous Materials, 445, 130584.

[7] Conte, M., Vasuri, F., Trisolino, G., Bellavista, E., Santoro, A., Degiovanni, A., … & Salvioli, S. (2013). Increased Plin2 expression in human skeletal muscle is associated with sarcopenia and muscle weakness. PLoS One, 8(8), e73709.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.