New research: Once this core organ ages, the functions of the whole body will "regress"

The liver is an important detoxification organ in the human body, and it also undertakes multiple tasks such as metabolism, detoxification, and energy storage. Recently, a paper was published in Nature Cell Biology, a subsidiary journal of Nature, revealing a new mechanism by which liver damage promotes multi-organ aging. The aging of the liver not only affects its own function, but may also become a "promoter" of systemic aging.

This discovery undoubtedly sounded the alarm for us: protecting the liver is not just for the liver itself, but also for delaying aging and maintaining the health of the whole body. So, what effects will liver aging bring? How can we protect the liver scientifically?

Liver aging is more harmful than you think

The core of liver aging lies in the aging of liver cells . These cells enter a state called "cellular senescence", which is characterized by cessation of division, decreased metabolic function, and a special secretion phenomenon - the senescence-associated secretory phenotype (SASP). Although these secreted substances can play a repair and protective role locally in the early stage, such as limiting the scope of damage or promoting wound healing, as the number of senescent cells gradually increases, the secretion of SASP also expands, and its negative effects begin to appear.

Studies have shown that the spread of this aging state may cause multiple organ dysfunction. In other words, severe liver aging will not only reduce the efficiency of the "metabolic factory", but may also affect other systems of the body, causing the whole body to fall into a vicious cycle of decline.

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How does liver aging spread throughout the body?

The issue of the "diffusibility" of liver aging is not simple; it involves the delivery of cellular secretions, the activation of signaling pathways, and the response mechanisms of other organs.

Studies have shown that senescent hepatocytes secrete a large number of senescence-associated secretory phenotype (SASP) factors, among which transforming growth factor-β (TGFβ) is considered a key mediator . These factors spread to distant organs through the blood circulation, affecting multiple systems such as the kidneys, brain, and lungs.

The researchers observed a chain reaction of multi-organ aging in a mouse model of hepatocyte-specific aging. The results showed that the number of cells expressing the cell cycle inhibitor p21 in the kidney increased significantly, and at the same time, renal function indicators such as plasma cystatin C levels increased, reflecting a decrease in kidney filtration efficiency.

Mdm2Hep (liver senescence) mice have impaired renal function as evidenced by elevated cystatin C levels and increased urinary amino acid excretion.

Not only that, but the brain and lungs were also similarly affected . In the experiment, the hippocampus of mice showed a significant increase in p21 expression, accompanied by a decline in cognitive function.

For example, in the Y-maze test, the time spent exploring the new arm in mice induced by hepatocyte aging was significantly reduced compared with the control group (from 50% to about 20%). This decline in cognitive function is closely related to neuronal dysfunction in the hippocampus. In the lung tissue, signs of cellular fibrosis also gradually appeared, suggesting that lung aging may be one of the long-term effects of liver aging.

Increased p21 expression in the brain and lungs of Mdm2Hep mice

The study found that the level of TGFβ in the blood of mice with liver aging was significantly increased. After blocking the TGFβ signaling pathway, the expression of p21 in the kidneys and brains of mice with liver aging was significantly reduced, indicating that the aging of these organs was significantly alleviated. This finding confirms that TGFβ plays an indispensable role in the systemic spread of liver aging.

bi: The results showed that the number of p21-positive cells in the kidneys, brain, and lungs of mice treated with TGFβR1 inhibitors was significantly reduced, and renal function was significantly improved.

At the same time, the researchers verified in a cohort of acute hepatitis patients that the expression levels of p21 and the DNA damage marker γH2AX were significantly increased in the liver tissue biopsy samples of the patients. The expression of these aging markers can not only distinguish the survival and non-survival outcomes of patients, but also is significantly correlated with the occurrence of multiple organ dysfunction.

For example, renal function indicators (such as serum creatinine levels) of non-surviving patients continued to deteriorate during hospitalization, and high expression of p21 in liver tissue was positively correlated with the severity of renal function deterioration. In addition, high expression of these markers was also associated with the occurrence of hepatic encephalopathy (such as cognitive impairment), suggesting that liver aging may affect brain function through systemic transmission mechanisms.

bc: The proportion of p21 and γH2AX positive cells in the non-survivor group was significantly higher than that in the survivor group, indicating that the degree of hepatocyte senescence is related to the prognosis of the disease.

de: Serum creatinine levels in the non-survivor group increased significantly over time, indicating worsening renal function. Hepatocyte p21 levels were associated with renal dysfunction.

f: Patients with higher p21 levels are more susceptible to hepatic encephalopathy, suggesting that hepatocyte senescence is associated with central nervous system dysfunction.

Through these experiments, the study revealed how liver aging breaks through the limitations of "local problems" and becomes a "core driving force" that affects the health of the whole body.

This also reminds us that protecting the liver is not only to maintain the function of a single organ, but also to prevent the whole body system from falling into the "aging chain". Especially during the holidays, the high-intensity metabolic burden is more likely to aggravate this diffusion process. We need to pay special attention to diet and lifestyle habits to avoid unnecessary health risks.

This protects our liver

In order to protect the liver, it is particularly important to scientifically manage diet and lifestyle habits. Through some simple adjustments, you can effectively reduce the burden on the liver and delay its aging process.

1

Eating habits

In terms of diet, you should pay attention to a balanced diet and avoid foods high in sugar, fat, and salt, especially excessive intake of greasy foods and desserts , to reduce the metabolic pressure on the liver. It is best not to smoke or drink.

2

Lifestyle

In terms of lifestyle, maintaining a regular work and rest schedule is the key to protecting the liver. Staying up late for a long time will disrupt the liver's biological rhythm and reduce its repair ability. Moderate exercise can help enhance metabolism, but high-intensity exercise should be avoided to avoid causing oxidative stress. In addition, managing emotions and reducing stress can also significantly improve the overall condition of the liver.

3

Regular medical check-ups

If conditions permit, regular physical examinations are a good choice, especially focusing on liver function indicators and potential fatty liver or inflammation. At the same time, people with drinking habits can try to set one or two "no alcohol days" a week to give the liver more time to repair.

A healthy liver is the foundation of a high-quality life. While enjoying the upcoming Spring Festival reunion, a scientific diet and lifestyle can reduce the burden on the liver and make the celebration more carefree.

References

[1]Kiourtis C, Terradas-Terradas M, Gee LM, et al. Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ. Nat Cell Biol. 2024;26(12):2075-2083.

[2]https://www.nature.com/articles/s41556-024-01543-3

Planning and production

Author: Jiang Yongyuan, Master of Internal Medicine, Third Military Medical University

Reviewer: Yan Jie, Chief Physician of Liver Disease Center, Ditan Hospital, Associate Professor of Peking University School of Medicine

Special thanks to Tang Ruijun, Attending Physician, Assistant Researcher, Second Affiliated Hospital, Army Medical University

Planning丨Wang Mengru

Editor: Wang Mengru

Proofread by Xu Lailinlin