Discussing the relationship between hormetic neuronal stimulation and its effects on the germline.

1. NEURONS VS GERMLINE
MARIOS KYRIAZIS MD
NATIONAL GERONTOLOGY CENTRE, CYPRUS

2. DEFINITIONS OF ‘AGEING’
•In biology, ageing
is ‘the imperfect
repair of time-
related damage’.
•In a medical
sense, ageing is
‘time-related
dysfunction’.

3. TWO ELEMENTS IN AGEING
1. Τhe process of ageing itself (time-
related damage and the inability to
repair this damage). This leads to
clinical dysfunction.
2. Diseases that are manifestations of
this time-related dysfunction.

4. THE COMPLEXITY OF THE TREATMENT MUST
MATCH THE COMPLEXITY OF THE PROCESS WE
WANT TO TREAT
•End our current
thinking based
only on
magnification (i.e.
the study of
magnified cells,
tissues, enzymes,
DNA)
•Consider how
matters look in
miniaturisation
('zoom-out’)

5. SYSTEMS THINKING
• Non-additive determinism:
A system is not defined by the
sum of all of its individual
components, but there are
emergent properties that add
another layer of complexity in
the system’s behaviour
• Reciprocal Determinism:
Distinct biological and distinct
social factors influence each
other in a complex manner,
leading to results which may
be unnoticeable when only the
biological or only the social
aspects are considered in
isolation.

6. BIOLOGY OF AGEING
CELL
S
DNA
LYSOSOME
S
ABNORM
AL
PROTEINS
FREE
RADICALS
MITOCHONDR
IA
CROSS
LINKS

7. ELIMINATION OF AGEING
BIOLOG
Y
EPIGENETI
CS
LIFESTY
LE
REPAI
R
BIOMEDICI
NEREPRODUCTIO
N
GENDE
R
EVOLUTIO
N
CULTU
RE
ETHIC
S
CONFLICT
RESOLUTIO
N
RISKS
TECHNOLOG
Y
HYPER
CONNECTIO
N
GLOBAL
BRAIN
COMPLEXI
TY
SCIENCE
CYBERNETI
CS
SOCIET
Y
ENVIRON
MENT
SMAR
T
CITIE
S
POLITIC
S

8. TECHNOLOGY
• The pace of technological
developments is changing
society
• Implications on our biology

9. I CONCENTRATE ON TECHNOLOGY AND
CULTURE
TECHNOLOGY CULTURE

10. BOTH CONCEPTS ARE BASED
ON INFORMATION
A MEANINGFUL SET OF DATA OR PATTERNS WHICH INFLUENCE THE
FORMATION OR TRANSFORMATION OF OTHER DATA OR PATTERNS,
IN ORDER TO REDUCE UNCERTAINTY AND HELP ACHIEVE A GOAL

11. HORMESIS
An adaptive response of cells
and organisms to a moderate,
intermittent, challenge.
A low dose stimulation, high
dose inhibition.
Nutritional, physical, mental
and chemical challenges may
result in mild damage which
upregulates repair
mechanisms. In an attempt to
repair this damage, age-
related damage is also
repaired.

12. THE INDISPENSABLE SOMA HYPOTHESIS
• We live in an information-rich
technological ecosystem
• Hormetic-style activation of
neuronal stress response
• Enhancement of the function
of the neuron AND
downregulate the function of
the germline.
• A human-computer hybrid
entity is both biologically and
technologically robust, and
able to survive without any
age-related degeneration,
due to a shift of repair
resources from the germline
to the soma.

13. STRESSING THE BRAIN THROUGH TECHNOLOGY
MAY REDUCE AGE-RELATED DISEASE
A purposeful integration with
technology may initiate an
intentional change in human
evolution and result in the
eradication of age-related
dysfunction in participating
humans.
It appears inevitable that
technology is increasingly
taking over our lives. However,
it seems that it can also help
us avoid ageing and age-
related disease, in a way that
has not been described before.

14. INCREASE FLOW
OF INFORMATION
IN OUR BRAIN
• The information load of our modern
society represents one such positive
challenge, known as a ‘hormetic
stressor’. During hormesis, a low
dose of any given stimulus (a
challenge) can stimulate the
organism in a positive way and
result in health improvement,
whereas an excessive or suboptimal
exposure of the same stimulus can
result in damage and disease.
For example, when a positive
amount of information (i.e. not too
little and not too much, but just
pleasantly challenging) reaches our
neurons, these react by activating
the ‘neuronal stress response’. This
response aims to regulate the slight
stress caused by the challenge to the
neuron, and leaves the neuron
healthy and more ‘information-rich’.

15. NEURONAL
STRESS RESPONSE
• Age-related diseases happen because
most resources that repair biological
damage have been directed by
evolution to the germ line, in order to
assure a good repair and thus
continuation of the species, leaving
limited resources to repair the rest of
our body. Therefore, we age and die,
while our genes pass unharmed to the
next generation. But, the activation of
‘neuronal stress response’ diverts these
repair resources away from the germ
line and back to the neuron. Thus our
neurons (and we) remain healthy and
function for longer.
there is production of factors, such
as Protein kinase RNA-like
Endoplasmic Reticulum Kinase
(PERK), Activating Transcription
Factor 6 (ATF6), and Inositol-
Requiring kinase 1 (IRE1), which are
in direct competition with the germ
line – the cells and elements of our
sperm and eggs.

17. CROSS-TALK BETWEEN THE NEURON AND
THE GERMLINE
There are evolutionarily-conserved soma-to germline
communication pathways. E.g. somatic nuclear receptors (such
as the nhr-114 receptor) buffer against toxic dietary metabolites
and actively protect germline stem cells. The nhr-114 somatic
nuclear receptor acts as a detoxifier and shields germline stem
cells from damaging environmental stress. Evidence is now
gathering to suggest that this process is not unidirectional, with
resources flowing from soma to germline only. Instead, under
certain circumstances resources can flow from the germline back
to the soma.

18. GENETIC INJURY IN THE GERMLINE MAY INITIATE
PROTECTIVE EFFECTS, AND UP-REGULATES STRESS
RESISTANCE IN SOMATIC CELLS
• For instance, the ubiquitin-proteasome system in somatic cells
may be up-regulated through agents generated in the germline
such as the MAP (mitogen activated protein)-kinase homologue
MPK-1. This germ-initiated somatic protective response may
reflect a conserved propensity to reverse the trade-offs
between germ cell and somatic cell repair.

19. NEURONAL STRESS INDUCES APOPTOSIS IN
THE GERMLINE
This process is mediated by the IRE-1 (inositol-requiring enzyme
1) factor, an endoplasmic reticulum stress response sensor,
which then activates p53 and initiates the apoptotic cascade in
the germline. Phosphorylated IRE-1 also activates tumour-
necrosis factor (TNF)-receptor-associated factor 2 (TRAF2) which
is another apoptosis-initiating factor.
IRE-1 p53 APOPTOSIS
TRAF2

20. STRESS RESPONSE FACTORS INITIATED IN
NEURONS MAY APOPTOSISE GERMLINE
CELLS
• Stress response pathways may be activated in neurons through
cognitive stimulation, of the magnitude and type we encounter
in our modern technological society and then cause apoptotic
germline cell death.
• Germline cells may ‘retaliate’ in order to increase degeneration
of the neurons. In other words, germline factors initiate
degenerative sequences in neurons, and when these germline
factors are lost, neural degeneration decreases.

21. SPERMATOGONIAL STEM CELLS
MULTIPOTENT NEURAL
PRECURSORS CAN BE DERIVED
FROM MULTIPOTENT ADULT
GERM LINE STEM CELLS
• The resulting neurons can
achieve full maturation and
efficient integration within the
existing neural network. This
possibility (that the germline
may act as a source of fully
functional neurons), is
astounding.

22. SUMMARY • This reverses the existing natural
tendency for allocating repair
resources to the germ line, with the
neurons now becoming able to fully
repair any age-related damage, and
thus function better for longer.
* Information technology is
placing an increased cognitive
load on our brain. This
information has to be ‘information-
that-requires-action’, and not just
any trivial set of data.
* The resulting hormetic
(positive) stress places our
neurons under continual
pressure to repair themselves.

23. THANK YOU
MARIOS KYRIAZIS, DRMARIOS@LIVE.IT
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