Researchers here demonstrate that delivery of humanin to aged mice can improve cognitive function. Humanin appears to trigger increased levels of autophagy, the collection of processes responsible for recycling damaged proteins and cell structures. Increased autophagy is associated with many of the approaches shown to modestly slow aging in short-lived species such as nematodes, flies, and mice. These approaches largely involve applying mild stress to cells, such as via heat, lack of nutrients, or other methods, or directly triggering the signals that normally result from such stress. Increased autophagy for some period of time is the primary outcome.
One of the more important mechanisms by which autophagy influences aging may be the removal of damaged mitochondria. Swarms of mitochondria act as the power plants of the cell, producing chemical energy store molecules, but their function degrades with age. This is in part a reaction to rising levels of cellular damage, but it is also the case that a tiny fraction of mitochondria can malfunction dramatically due to DNA damage. This leads to errant behavior in cells that can damage the tissue environment. Greater recycling of mitochondria appears to reduce their dysfunction in aging, though nowhere near as much as we'd like it to. We have a good guide as to what happens when autophagy is upregulated in humans, namely the practice of calorie restriction. Far greater benefits than those realized via calorie restriction seem unlikely to arise through this set of mechanisms.
Humanin is the first member of a new class of peptides originating from small, alternative open reading frames within the mitochondrial genome. Since it was discovered, humanin has been shown to be neuroprotective in multiple in vitro and animal studies. The importance of the mitochondria in the etiology of Alzheimer's disease is becoming more apparent and evidence suggests that humanin protects from various insults both in cellular models and in vivo models of Alzheimer's disease. Because circulating humanin levels have been shown to decrease in humans as they age, humanin could also play a role in age-related cognitive decline although this has not been investigated.
Because humanin is encoded within the mitochondrial genome, mitochondrial genetics may influence the expression of humanin, which in turn may directly influence cognition during aging. In fact, many of the differences in disease incidence between haplogroups and ethnicities are in diseases that have been linked to humanin in animal models such as Alzheimer's, diabetes, and cardiovascular disease. Thus, in this study we examined the role of humanin in cognition and its use as a possible intervention across several experimental models and paradigms.
We show that humanin has neuroprotective effects both in vitro and in vivo. We further show that humanin administration is sufficient to prevent some of the normal behavioral and cognitive deficits that occur with age in common laboratory mice. This suggests that the decline in humanin seen with increasing age may be one of the reasons for the age-related decline in cognition and related physiological parameters.