Investigating the Role of GDF-10 in Brain Regeneration
Following a stroke, the survivors exhibit varying degrees of limited regeneration in the brain. Researchers are interested in finding reliable ways to enhance that process. Beyond the context of recovering from such injuries, it is important in the development of treatments for aging to be able to spur greater ongoing growth and regeneration in the aging brain:
Looking at brain tissue from mice, monkeys and humans, scientists have found that a molecule known as growth and differentiation factor 10 (GDF10) is a key player in repair mechanisms, such as axonal sprouting, that are activated following stroke. During axonal sprouting, healthy neurons send out new projections ("sprouts") that re-establish some of the connections lost or damaged during the stroke and form new ones, resulting in partial recovery. Before this study, it was unknown what triggered axonal sprouting. Previous studies suggested that GDF10 was involved in the early stages of axonal sprouting, but its exact role in the process was unclear. Examining animal models of stroke as well as human autopsy tissue, researchers found that GDF10 was activated very early after stroke. Then, using rodent and human neurons in a dish, the researchers tested the effect of GDF10 on the length of axons, the neuronal projections that carry messages between brain cells. They discovered that GDF10 stimulated axonal growth and increased the length of the axons.Researchers treated mouse models of stroke with GDF10 and had the animals perform various motor tasks to test recovery. The results suggested that increasing levels of GDF10 were associated with significantly faster recovery after stroke. When the researchers blocked GDF10, the animals did not perform as well on the motor tasks, suggesting the repair mechanisms were impaired - and that the natural levels of GDF10 in the brain represent a signal for recovery. It has been widely believed that mechanisms of brain repair are similar to those that occur during development. The team conducted comprehensive analyses to compare the effects of GDF10 on genes related to stroke repair with genes involved in development and learning and memory, processes that result in connections forming between neurons. Surprisingly, there was little similarity. The findings revealed that GDF10 affected entirely different genes following stroke than those involved in development or learning and memory. "We found that regeneration is a unique program in the brain that occurs after injury. It is not simply Development 2.0, using the same mechanisms that take place when the nervous system is forming."
Hello all!
This is very interesting and it ressembles IGF-1 effect. Both GDF-10 and IGF1/IGF-1r act
in linked concert. Activating IGF-1 receptors in brain neuronal tissues elicits a
survival signal/growth signal of axonal/neuronal sprouting)). IGF-1 receptors activation in the brain, with
GDF, IGF and BDNF factors, help for neuron/axon/synapse/astrocyte/dendrite survival in face of brain damage.
Centenarians that are more demented, cognitively more affected or with memory loss show reduced brain levels
of IGF-1
This old 2011 (1.) study on axonal sprouting talks about GDF-10 and IGF-1,
Quotes from it :
''Fourteen of 21 genes that were upregulated in aged sprouting neurons versus non-sprouting neurons at day 7 in the array data set were also upregulated by qRT-PCR:
..., chimaerin-1 (chimerin-1), Gdf10 (growth differentiation factor 10), Gpc3 (glypican-3), Igf1, ... ''
''After stroke, IGF1 was induced in glial fibrillary acidic protein (GFAP)-positive reactive astrocytes in peri-infarct cortex of the young adult18.
Unexpectedly, stroke in aged mice induced IGF1 mostly in cells positive for the neuronal marker NeuN in peri-infarct cortex.''
''Igf1 and osteopontin were the most differentially regulated genes in aged sprouting neurons, with 20- and 12-fold induction compared to the control expression level of non-sprouting neurons. ''
Study 3. and 4.:
'' Interestingly, centenarians with lower IGF-1 levels had a higher prevalence of definitive dementia...
It is also suggested that low levels of serum IGF-1 may be involved in the progression of dementia in the oldest old.''
''The fall in IGF-I levels with aging correlates with cognitive decline and it has been suggested that IGF-I plays a role in the development of dementia. IGF-I is highly expressed within the brain and is essential for normal brain development. IGF-I has anti-apoptotic and neuroprotective effects and promotes projection neuron growth, dendritic arborization and synaptogenesis. Collectively, these data are consistent with a causal link between the age-related decline in GH and IGF-I levels and cognitive deficits in older persons.''
Increased activation of IGF-1 receptors is a real paradox, IGF is important for brain development, muscle building and maintenance, but clearly
it alters the whole somatotropic/SIRTUIN/FOXO/Insulin neuro-endocrine signaling (see study 5.). It accelerates Growth of the body and that is double-edged sword (long-lived animals are rarely accelerated in growth, humans are actually very slow to mature sexually (many years before reach to sexual reproduction)). It is a direct consequence of sex steroid/thyroid/Growth hormones (pituitary/gonatropin/somatotropin...) by the endrocrine systems
who regulate the actual Growth of an animal, Growth seems to directly translate to MLSP (maximum lifespan). Slow-growth animals with extreme lifespans such Giant Turles, Polar Clams and Bowhead Whales all share slow sexual maturation/slow growth and an insulin pathway that is highly preserved/evolved genetically for longevity. IGF-1R, in the neuro-endocrine sexual hormonal growth control of lifespan and rest of brain, is a double-edge damocles sword
that controls Insulin longevity hormone signals (DAF-16, FOXO, SIRTUINs) that they themselves control growth and speed of aging (not necessarily only body growth...bowhead whales are immense! but Cell Growth, studies showed through mTOR, IGF, endocrine/somatotrophic hormone brain axis that this controls the cell's very size/growth, aged mother cells enlarge (lipofuscin accumulation + cell size is an actual genetic 'growth/growing' signal that equals 'to aging', at a certain point the cell reaches a certain maximum size (if I remember it was 17.4 micron max size) and activates death program to die after 17.4 micron cell size is reached)
Every intervention that damages these cells (through accelerated growth/hypertrophy) results in growing enlarged cells to a max size and then their death (quicker growth or slower depending on damage accrual speed). What's more is this IGF-1 receptor activation is dramatically activated by AGEs (advanced glycation end products through Akt/ERK/MEK activation) whom they are directly linked to MLSP (maximum lifespan, see study 5.) and glucose glycation glycosylation; meaning glucose and especially fructose are the upstream effectors of this brain IGF-1r Growth Longevity Lifespan reduction cascade.
6. 'Activation of Akt by advanced glycation end products (AGEs): involvement of IGF- 1 receptor and caveolin-1'.
Clearly, GDF-10 (through GH receptors/GD receptors) is important for brain neuron/axonal sprouting but like IGF-1 activating IGF-1 receptors, it's a fine balance act between aging rapidly with Growth Hormones (excess growth) vs aging slowly with reduced IGF-1 receptor activation but at a mental cost.
Perhaps, there can be a 'in between' where it is Low Adequate IGF-1/r for Adequate Brain Function and For Longer Longevity at the same time (through reduced Insulin Growth Axis-Signaling/Diabetes/Reduced Oxidative Stress/Redox Homeostasis, etc...)
1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059556
2. http://www.ncbi.nlm.nih.gov/pubmed/17057708
3. http://www.ncbi.nlm.nih.gov/pubmed/11213280
4. http://www.ncbi.nlm.nih.gov/pubmed/16760634
5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651522
6. http://www.ncbi.nlm.nih.gov/pubmed/23472139
7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2573928
8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568972