Humanin reduced liver injury in a severe infection study

Researchers first measured Humanin in blood from 20 patients with a hypervirulent Klebsiella pneumoniae infection and 20 matched healthy people. The patients had higher Humanin levels than the controls ¹. That difference may be a stress response, but the study could not show whether the higher level was helpful or harmful.

In mice, researchers gave Humanin into the abdomen for five days before an intravenous challenge with the bacteria. The two doses were 2.5 or 5 milligrams per kilogram daily ¹. Mice that received Humanin had less visible liver injury and lower blood levels of ALT and AST, liver enzymes that leak out when liver cells are damaged ¹. They also had lower markers of inflammation and less activity of NF-κB, a protein complex that turns on inflammatory genes ¹. The higher dose reduced these changes more than the lower dose, and it also extended survival ¹. The RNA analysis showed that inflammatory pathways were less active, but the study leaves open exactly which molecule Humanin acted on ¹.

Diabetic nephropathy is kidney damage that can develop in people with longstanding diabetes, and it is a leading cause of advanced kidney failure ². A mouse study used a high-fat diet plus streptozotocin, a chemical that damages insulin-producing cells, to model this kidney disease ². Some mice also received HNG, a more potent analog of Humanin ².

The high-dose HNG group had a 49 percent lower amount of albumin in the urine, compared with untreated diabetic mice ². Albumin in urine is a sign that the kidney's filters are leaking. The study also found a 52 percent reduction in p-MLKL, a protein marker of necroptosis, a form of cell death that spills cell contents and drives inflammation ². The authors traced this protection to less movement of BAX, a protein that can poke holes in mitochondria, and less escape of mitochondrial DNA into the cell fluid, where it can trigger inflammatory alarms ². These protective effects also appeared in a separate genetic mouse model of diabetes and in human kidney tubule cells exposed to high sugar and a fatty acid in the lab ².

Renal ischemia-reperfusion injury happens when the kidney's blood supply is briefly cut off and then restored. The return of blood can cause fresh damage through reactive oxygen species, chemically reactive molecules that damage cells, and inflammation ³. In rats, researchers clamped the renal artery for 45 minutes and then allowed 24 hours of reperfusion ³. HNG was given through a vein 10 minutes before blood flow returned ³.

Rats that received HNG had higher levels of the antioxidant glutathione and higher activity of superoxide dismutase, an enzyme that clears reactive oxygen species ³. They also had lower myeloperoxidase, a marker of inflammatory cell activity, and lower malondialdehyde, a byproduct of oxidative damage ³. Energy production was better preserved, with higher ATP and higher mitochondrial complex I activity ³. The percentage of cells dying by apoptosis, a controlled cell death process, was also lower ³. These benefits appeared to involve STAT3 and ERK1/2, two proteins that promote cell survival ³. Standard kidney function tests, blood urea nitrogen and serum creatinine, were elevated after injury and did not improve with HNG in this short 24-hour study ³.

Humanin is a small peptide made naturally in mitochondria, the energy powerhouses of cells ⁴. Early research showed it protected brain cells from Alzheimer's-related toxicity and reduced stroke damage in mice ⁶. Since then, animal studies have shown protective effects in acute lung injury ⁸, in blood vessel linings exposed to high glucose ⁹, and in metabolic hormone balance in diabetic mice ¹⁰. Human observational data also link higher natural Humanin levels to lower oxidative stress and better metabolic health ¹¹.

The three new papers add two organ systems, liver infection and two different kidney injuries, to that list. They also share a theme: Humanin or its analog HNG appears to reduce inflammation and cell death when tissues are under stress ¹.

These studies leave open several questions. The liver study found higher Humanin in infected patients, but that could reflect the body's stress response rather than protection ¹. The molecular target for Humanin in infection is not identified ¹. In the kidney blood flow study, the lack of improvement in blood urea nitrogen and serum creatinine means the better antioxidant markers may not translate to better kidney function in that window ³. No human trial has tested Humanin as a treatment for any condition ¹¹. The long-term safety of Humanin or HNG in people is unknown ¹⁴.

In the research so far, new animal studies show less organ injury, but no human trial has confirmed that Humanin protects people.