Researchers have improved multiple health metrics in prematurely aged mice by re-establishing the production of neuropeptide Y in the hypothalamus [1].
An essential protein
Age-related decline in the function of the hypothalamus, a core region of the brain, has been suggested to be a “key factor in the development of whole-body aging” [2]. Due to its essential role and implication in several aging-related processes, the hypothalamus may be a target for lifespan- and healthspan-extending therapeutic strategies.
The authors of this study focused specifically on hypothalamic neuropeptide Y (NPY). Several studies suggest that neuropeptide Y plays a role in lifespan through its involvement in lifespan-extending processes such as autophagy induction [3] and stress resistance [4], and it appears to play an essential role in caloric restriction-induced lifespan extension [5, 6]. Decreased levels have been connected to neurodegenerative diseases [7]. Therefore, the authors hypothesized whether re-establishing hypothalamic neuropeptide Y levels might slow down aging.
Aging too quickly
For this study, the researchers used animals that lack a gene encoding the protein Zmpste24 (Z24-KO), and this lack results in accelerated aging and premature death. Z24-KO mice have multiple defects in skin, bone, cardiovascular tissues, and skeletal muscles, similar to those observed in human accelerated aging processes. Therefore, the authors decided to test if their hypothalami exhibit the same changes as the hypothalami of naturally aged mice.
They tested an area of the hypothalamus called the arcuate nucleus (ARC), which contains neurons that release neuropeptide Y. They found lower levels of neuropeptide Y compared to age-matched wild-type mice and lower levels of a neuronal marker called NeuN, suggesting neuronal aging and fewer hypothalamic neurons.
Markers connected to neuroinflammation were also altered. The authors observed increased levels of a gliosis marker in Z24-KO mice. Gliosis is a process that occurs in glial cells (non-neuronal cells located in the central nervous system) in response to damage. Therefore, an increase in gliosis suggests neuroinflammation. On the other hand, a marker showing the activity of microglia, the immune cells of the brain, decreased in Z24-KO mice. This, according to the authors, suggests that immune response capacity is impaired.
Restoring youth
To re-establish decreased neuropeptide Y levels, the researchers used a genetically modified adeno-associated virus (AAV) that causes an increase in the expression of neuropeptide Y (AAV-NPY) and injected it into the mice. The virus increased neuropeptide Y in the ARC for at least four months, which is when the mice were sacrificed to analyze their organs.
The researchers tested the AAV-treated Z24-KO mice for the same biomarkers as the untreated Z24-KO mice. They observed an increase in NeuN and a reduction of the gliosis biomarker that is normally elevated in these mice. However, the biomarker of microglial immune capacity didn’t significantly change. Overall, AAV treatment made the brains of Z24-KO mice similar to those of age-matched wild-type mice, suggesting that neuropeptide Y plays a role in reducing neuroinflammation.
Further testing suggested positive changes in aging-related processes. The authors observed a reduction in NF-κB, a protein that increases with aging and is associated with neuroinflammation in the hypothalamus [8]. Other positive effects were a decrease in a marker of tau pathology, which is associated with neurodegenerative diseases [9], and an increase in autophagy, a process that plays an essential role in longevity.
Better looks and healthier minds
The authors also report positive changes in body weight, body composition, mobility, vitality, and fur among the virus-treated animals. The treatment also showed neuroprotective effects, as the spatial memory improvements accompanied physical health improvements, but there were no significant differences in locomotor activity.
One of the characteristics of the prematurely aged Z24-KO mice is lipodystrophy. This condition results in the organism losing fat from some parts of the body, including under the skin surface of different body parts, while gaining it in others, such as the liver.
The AAV-treated mice had fewer lipodystrophy symptoms. The treatment resulted in a thicker outermost skin layer (epidermis) and thicker layers of under-skin (subcutaneous) fat, probably resulting from increased proliferation of fat cells as suggested by increased levels of a cell proliferation marker. It also increases skin collagen, which decreases with age. Autophagy markers in the skin indicated increased autophagic activity, suggesting better cellular health.
Liver structure was also improved in the Z24-KO mice after treatment. The researchers observed increased cell proliferation, which might indicate improved liver protection and regeneration, a decrease in cellular death by apoptosis, and increased autophagic activity in the liver, suggesting better cellular health.
There were no differences between treated and untreated mice in different parameters of kidney health and heart structure, but heart cells showed improved cellular health.
Promising, but there are still many unknowns
Overall, this study’s results suggest that re-establishing neuropeptide Y has a positive effect on aging-associated hypothalamus-related symptoms. However, in most of the experiments performed, the researchers compared untreated, prematurely aged mice to prematurely aged mice treated with a virus expressing neuropeptide Y. It would be beneficial if a wild-type control was included, as this would allow for assessing whether the observed changes make the prematurely aged mice more similar to wild-type mice or if the changes are significant but modest.
Additionally, long-term studies are essential to determine the long-lasting effects and side effects of this approach, whether it induces the desired amount of neuropeptide Y expression, and how improvements in different biomarkers of cellular health translate to increases of healthspan and lifespan.
Literature
[1] Ferreira-Marques, M., Carmo-Silva, S., Pereira, J., Botelho, M., Nóbrega, C., López-Otín, C., de Almeida, L. P., Aveleira, C. A., & Cavadas, C. (2025). Restoring neuropetide Y levels in the hypothalamus ameliorates premature aging phenotype in mice. GeroScience, 10.1007/s11357-025-01574-0. Advance online publication.
[2] Kim, K., & Choe, H. K. (2019). Role of hypothalamus in aging and its underlying cellular mechanisms. Mechanisms of ageing and development, 177, 74–79.
[3] Aveleira, C. A., Botelho, M., Carmo-Silva, S., Pascoal, J. F., Ferreira-Marques, M., Nóbrega, C., Cortes, L., Valero, J., Sousa-Ferreira, L., Álvaro, A. R., Santana, M., Kügler, S., Pereira de Almeida, L., & Cavadas, C. (2015). Neuropeptide Y stimulates autophagy in hypothalamic neurons. Proceedings of the National Academy of Sciences of the United States of America, 112(13), E1642–E1651.
[4] Michalkiewicz, M., Knestaut, K. M., Bytchkova, E. Y., & Michalkiewicz, T. (2003). Hypotension and reduced catecholamines in neuropeptide Y transgenic rats. Hypertension (Dallas, Tex. : 1979), 41(5), 1056–1062.
[5] Chiba, T., Tamashiro, Y., Park, D., Kusudo, T., Fujie, R., Komatsu, T., Kim, S. E., Park, S., Hayashi, H., Mori, R., Yamashita, H., Chung, H. Y., & Shimokawa, I. (2014). A key role for neuropeptide Y in lifespan extension and cancer suppression via dietary restriction. Scientific reports, 4, 4517.
[6] de Rijke, C. E., Hillebrand, J. J., Verhagen, L. A., Roeling, T. A., & Adan, R. A. (2005). Hypothalamic neuropeptide expression following chronic food restriction in sedentary and wheel-running rats. Journal of molecular endocrinology, 35(2), 381–390.
[7] Duarte-Neves, J., Pereira de Almeida, L., & Cavadas, C. (2016). Neuropeptide Y (NPY) as a therapeutic target for neurodegenerative diseases. Neurobiology of disease, 95, 210–224.
[8] Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., & Cai, D. (2013). Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature, 497(7448), 211–216.
[9] Samudra, N., Lane-Donovan, C., VandeVrede, L., & Boxer, A. L. (2023). Tau pathology in neurodegenerative disease: disease mechanisms and therapeutic avenues. The Journal of clinical investigation, 133(12), e168553.