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INNOSC Theranostics and
Pharmacological Sciences AMPK in metabolism, energy and aging

consumed). Another interesting observation is the low level inhibitors or caloric restriction led to similar results,
of leptin following metformin treatment, which may explain significantly increasing the life expectancy of those
its anorexic effect. This effect could be due to the sensitization organisms. 99,100 In contrast, continuous mTORC1 blockade
of the hypothalamus to leptin, potentially through an can lead to the onset of cardiomyopathy and rapid progression
increase in the number of specific receptors in this region. to heart failure, hence impairing life expectancy. 101
The hypothalamus plays a crucial role in regulating energy Thus, the autophagic process is crucial for promoting
balance, making it a key region for this effect. Regarding the health and longevity. Disruptions in this mechanism can
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anti-inflammatory effect of metformin, various studies show contribute to the development of age-related diseases. 102-104
a positive effect, following a reduction in cytokines such as
interleukin-6, tumor necrosis factor-α, nuclear factor-kappa Substances known to be longevity promoters are
B, but this remains a hypothesis at the research stage. 91-93 divided into three categories according to their mode of
action:
A mechanism for eliminating aged cellular organelles • Those that have demonstrated anti-aging effect but
or damaged proteins can be achieved through autophagy. lack conclusive evidence for this ability;
This process can be activated through the administration • Those suggested to prolong youth by preventing
of exogenous agents, such as rapamycin, resveratrol, or delaying the onset or progression of age-related
nicotinamide derivatives (Vitamin B ), metformin, diseases, though their influence on the aging process
3
urolithin A or spermidine, compounds thought to delay itself has not been proven;
aging, and even extend lifespan. 94,95 • Those that reverse the aging mechanism, at least under
Instead, the body has several defense and preservation certain conditions, thereby prolonging youth;
mechanisms, with autophagy, which represents a process of 4. AMPK at the hypothalamus level
“purification”. This involves recycling outdated or damaged
protein structures, including cellular organelles, by forming AMPK in the central nervous system is known to control
autophagosomes, which later fuse with lysosomes. 96,97 nutrient intake and restore energy balance which is activated
Autophagy is the cell’s survival mechanism, regulated under pathophysiological conditions. The neuroprotective
by various signaling pathways, with the AMPK-mTOR effect of metformin is thought to result from increased
system being one of the most important. neuronal sensitivity to insulin, as poor insulin signaling
in the brain is associated with an increased risk of
There are three types of autophagy described: neurodegenerative diseases. AMPK integrates peripheral
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• Macro-autophagy signals, such as metabolites and hormones, through neural
• Micro-autophagy networks. Following the integration of signals at the level
• Chaperone protein-mediated autophagy of the hypothalamus, it causes the sensation of hunger,
In macro-autophagy, the autophagosome represents the the production of heat (thermogenesis) and energy by
catalytic unit. It is formed from an insulating membrane mobilizing brown and white adipose tissue.
in which a small part of the cytoplasm, soluble molecules, Studies have identified specific hypothalamic nuclei
and cell organelles are included. The next step involves where AMPK is expressed, including the arcuate,
fusion with lysosomes to form autolysosomal units, where dorsomedial, paraventricular, ventromedial, and lateral
the degradation of internal contents take place. hypothalamic nuclei. Unlike AMPK in the rest of the body,
Micro-autophagy, on the other hand, occurs through hypothalamic AMPK activation increases food intake and
the engulfment of small components by the lysosome. causes weight gain, while its inhibition reduces appetite
3
Thus, significant amounts of cytosolic material, including and weight.
protein molecules are incorporated into this complex. Using genetic models, it was shown that by blocking
the dominant negative isoform of hypothalamic AMPKα
The third type of autophagy, chaperone protein-
mediated autophagy, does not involve membrane decreases the messenger RNA (mRNA) expression of
orexigenic neuropeptides, such as agouti-related protein
reorganization. Instead, cytosolic proteins are selectively (AgRP) and neuropeptide Y (NPY). Conversely, increased
recognized and translocated to the lysosomal membrane expression of the active isoform of AMPKα increases
by the chaperone protein Hsc7 together with its AgRP and NPY synthesis in the arcuate nucleus. New
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co-chaperones. The unfolded proteins are then transported data also indicate that AMPK modulates autophagy,
to the lysosome through a multimeric complex. 98 thereby controlling the production of both NPY and
Experimental models in C. elegans, Drosophila, and proopiomelanocortin (POMC). Both orexigenic and
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rodents have demonstrated that mTOR growth factor anorexigenic hormones control appetite through their

Volume 8 Issue 2 (2025) 8 doi: 10.36922/itps.4852