Relation between cell scencence and death and health state (aging and cancer in addition to antiaging drugs

1. Cell scencence and death types And Anti-
aging Drugs
BY
Mohie-Aldien A Sherif
Professor of Pharmacology, Faculty of Medicine, Benha University, Benha, Egypt

2. Abreviation:↑=increase;↓= decrease; / = and-or; ±: may be a type of RCD; ACD :Accidental cell death
;Akt, a survival kinase = protein kinase B or PKB) that, when activated, indirectly enhances glucose
metabolism and suppresses Autophagy through the mTOR kinase; HDM2, P53 inactivator; AMPK, AMP-
activated protein kinase; AIFM1:Apoptosis-inducing factor 1, mitochondrial;Atg autophagy-related
genes. BKC: big potassium channels Bcl-2, B-cell lymphoma 2; BH, Bcl-2 homology; Bcl-xl; crmA, cytokine
response modifier; Bax:Bcl-2-associated X protein(a pro-apoptotic protein); bid, BH3 interacting domain
death agonist; Caspases = cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-
directed proteases; Ca: Calcium; D:Dopamin; DAMPs, Damage-associated molecular patterns which initiate
Extracellular
=
ECM
reticulum
endoplasmic
:
ER
;
inflammatory response
and perpetuate a noninfectious
matrix; FasL, death factors ; ); FOXO, Forkhead transcription factor;G:Glutamate; G.F., Growth factors;
IAP, Inhibitors of apoptosis proteins; JNKs , Jun N-terminal kinases in signaling events underlying tumor
genesis & tumor progression; Keap1: Kelch-like ECH-associated protein 1 ; MLKL ,mixed-lineage kinase
domain-like protein , MOMP, Mitochondrial outer membrane permeabilization; mTORC1, mammalian (or
mechanistic) target of rapamycin complex 1; NLRP3- inflammasome, a multimeric protein complex that
initiates an inflammatory form of cell death and triggers the release of proinflammatory cytokines IL-1β and
IL-18; RIP,r receptor-interacting serine/threonine-protein Rbp: retinoblastoma protein→ ↑DNA replication;
SIRT1, Sirtuin type 1 (silent information Regulator type 1; PTEN, tumor suppressor phosphatase, and
tensin homolog; DNMT Human DNA Methyltransferase; pRb, retinoblastoma protein→ ↑DNA replication;
p21&P16 ,cyclin-dependent kinase inhibitor ;CGRP: calcitonin gene-related protein; PUMA, p53-
upregulated modulator of apoptosis; CCN, matricellular proteins → modulating inflammation and tissue
injury repair, SMAC, second mitochondria-derived activator of caspases HSCs, Hematopoietic stem cells;
MPTP:mitochondrial permeability transition pores; MSCS, Mesenchymal stem cells; IESCs, intestinal
epithelial stem cells; HGS, human monoclonal agonistic antibodies; PARP, Poly (ADP-ribose) polymerase;;
;
proteases
, and
growth factors
,
cytokines
inflammatory
Phenotype consisting of
Secretory
,Senescence
SASP
RBp= retinoblastoma protein SAG= senescence-associated –galactosidase ; SACF,senescence-associated
heterochromatin foci; TNF, tumor necrosis factor; TRAIL,TNF-related apoptosis-inducing factor Legend ;
TCD, tolerogenic cell death ;USP , ubiquitin-specific proteases (USP10,13 control the levels of p53.) .

3. Timeline of the terms used in cell death research
Cell Research volume 29, pages347–364 (2019)

4. B) CELL DEATH
1) Accidental cell death (ACD )/necrosis).
2) Program/Regulated cell death (PCD/RCD
A) cellular senescence is a pathophysiological
process through which the cells permanently lose
their proliferative capacity while remaining viable
and metabolically active

5. Senescence
(Irreversible
Cell arrest)
Regulated/ Programed cell death (RCD/PCD) ACD
Necrosis
Vacuoles presented Apopt-
osis
Ferop-
tosis
Immune reactive
Autophagy Paraptosis Necroptosis Pyroptosis
Targe
t cell
Normal useful
cells
Dysfunctio
nal
Organelles
Apoptosis
resistant
Normal
but useless
cell
↑ lipid
perox-
idation
cells
Damage/Infected cells useful
contiguous
cells.
Mor
phol
ogic-
al
chan
ges
Extensive
vacuoliz-
ation of
cytoplasm;
loss ;
mitochondra
Swelling
Double
membrane
autophago
some
around
damaged
organelle
Dilated mit
ochondria
and ER →
vacules→
multi
memb-
ranous
bodies
Cell
rounding;
nuclear
condensat
ion;
membran
e
blebbing;
apoptotic
body
formation
; DNA
fragmenta
tion)
ROS,
iron
accu-
mulatio
n , lipid
peroxid
ea tion,
small
mitocho
n-dria
with
outer
membra
ne
rupture.
Membrane damaging
(pore formation) by
Gasdermin D (GSDMD
and MLKL proteins →
cell lyses
Liquefa-
ctive,
coagulative
, caseous,
fat,
fibrinoid,
and
gangrenous
.

6. Chronic (Late), irreversible Inflammatory Senescence
A senescence-associated secretory phenotype (SASP)
+ Inflammation

7. Other forms of necrosis:
Alkaliptosis ±: Intracellular alkalinization ; ↑NF-κB;
2nd necrosis: cytolysis 2nd to apoptosis when dying cell fail to be removed
by heterophagy

8. Autophagy
Dilated
Mitochondria
ptosis
Para
Dilated
endoplasmic
reticulum
(ER)
ER derived
vacuoles
1) Vacuolar Program/Regulated cell death.
Macro-
pinosome
derived
vacuole.
cell
swelling
Methuosis
membrane rupture
Entosis: invasion of
a living cell into
another cell's
cytoplasm→ inner cell
death (antitumor) or
Outer cell multin ucl -
eated and nutrient gain
post tumorgenic .
Autosis
Membrane rupture
Ballooning of
peri-nuclear
space
Autophagosome
induced by hypoxia-ischemia ,glucose
starvation , matrix detachment of adherent
cells hepatocyte injury. Entosis is Na+ ,K+ -
ATPase dependent and cardiac glycosides
inhibit it. Irreversible Na+/ K+AT Pase.
degeneration
NB:Mitophagy :
autophagic mitochon-
dria degradation
was defined in glioblastoma cells
after ectopic expression of
hyperactivated Ras proteins

9. 2) Morphology of some Mitochondrial related cell death
permeability transition pore complex (PTPC)
Biomolecules 2020, 10(7), 998; https://doi.org/10.3390/biom10070998

10. Cell Research volume 29, pages347–364 (2019)
Extrinsic and intrinsic apoptosis.
OTHER FORMS Of Apoptosis:
Anoikis:due to ina- ppropriate
cell- matrix interactions.
Mitoptosis:mitocho-ndrial elimination
(MPTPopening )
Mitotic intrinsic apo-ptosis/
catastrophy.

11. Oxytosis: ROS-dependent; activation of KEAP1,lack of nuclear translocation of AIFM1

12. Immune/infection related cell death:

13. Senescence
(Irreversible
Cell arrest)
Regulated/ Programed cell death (RCD/PCD) ACD
Necrosis
Vacules presented Apoptosis Feroptosis Immune reactive
Autophagy Paraptosis Necropto
sis
Pyroptosi
s
Mech
anism
*↑p53→ ↑p16 ,
p21 → ↓ RBp
→ ↓cell cycle
at G1
*release apop-
totic inhibitors
* release SASP
affect other
cells → age-
related diseases
↑mTOR/
AMP kinase
→ phos-
phorylation
Atg1) leads
to:
regeneration/
repair. or
cell death
depend on
BKC .
caspase-9
Intrinsic (I am
damaged , I
must die):↑
P53 activity→
mitochondria
release
cytochrome C
→ ↑ caspases
→ Death
Extrinsic
(abnormal /
dangerous /
infected, you
must die): ↑
Fas.L ; TNF;
TRAIL
binding
↑ROS ,
↓antio
xidant
system →
iron-
catalyzed
process of
lipid
peroxidation
TNF
receptor
signaling;
JNK
activation
; RIP1/
RIP3
necro-
some
Nod-like
receptors
Caspase
1-
dependen
t
pyropto-
some
Inflamma
-some.
↑Ca2+
influx →
cell
swelling
(oncosis) /
lyses
membrane
→ spill out
contents ;
mitoch
ondrial
rupture ;
Chroma tin
clumps
;DNA
degradation
Energy Catabolic
process
ATP-
dependent
ATP-
dependent
ATP-
dependent
ATPdepend
ent
ATP-dependent No
Inflam
mation
Yes (long term) No No No or yes
(↑DAMPs)
Yes Yes Yes

14. Senescence
(Irreversible
Cell arrest)
Regulated/ Programed cell death (RCD/PCD) ACD
Necrosis
Vacules presented Apoptosis Feroptosis Immune reactive
Autophagy Paraptosis Necropto
sis
Pyroptosi
s
Tissue
respons
e
*Cleared by
immune system
→ ↓tumor
homeostasis;
regen-eration &
healing →↑
longevity.
*Accumulate &
release soluble
SASP → aging;
cancer,
degenerative
diseases.
It often helps
survival:
*adaptive
response to
stress, e.g.
extreme
starvation by
mainta-ining
cellular
energy
* ↓ dysfuncti-
onal mito-
chondria
accumul-
ation, ROS&
NLRP3
inflam-
masome
→↓aging
fragments is
phagocy-
tosis by
neighbori-ng
cells or
macroph-
ages
Physiological:
phagocytosis
of damaged
cells ; tumor
suppression
tissue
remodeling;
embryo
development.
Pathological:
excess
apoptosis →
neuro-
degenerative
diseases
important
regulatory
role in
diseases e.g
neurodegen
erative,canc
er, diabetes
Protect the host
against microbial
pathogens; their
dysregulation has
been implicated in a
variety of
autoimmune and
auto-inflammatory
conditions
Phagocytosi
s by
adjacent
cells or mac
ro phages;
↑inflamma-
tory
response
Energy Catabolic
process
ATP-
dependent
ATP-
dependent
ATP-
dependent
ATPdepend
ent
ATP-dependent No
Inflam
mation
Yes (long term) No No No or yes
(↑DAMPs)
Yes Yes Yes

15. Core molecular mechanism of non-apoptotic regulated cell death
Cell Research volume 29, pages347–364 (2019)

16. Cell Research volume 29, pages347–364 (2019)
Central role of TMEM173 in inflammation, immunity, and cell death

17. Senescence
(Irreversible
Cell arrest)
Regulated/ Programed cell death (RCD/PCD) ACD
Necrosis
Vacules presented Apoptosis Feropto
sis
Immune reactive
Autophagy Paraptosis Necroptosis Pyroptosis
Induce
rs
DNA damage in
response to mild
stress-free
radicals/
telomere
shortening;
oncogene
(RAS).
Moderate
stress, Atg
induction:
Inhibitors of
tyrosin kinase
mTOR,
proteas-ome
and histone
deacetylase.
Curcumin
Paclitaxel,
Hesperidin
Honokiol,Cel
astrol,Tunica
mycin
cyclosporin
A,corticoster
oid.
Physiological:
Cytokines
(TNF,TGFß,Fa
sL);trans -
mitters (G,D);
cortisone.
Moderate
Stress:
Drugs:olemers
an,aresenic
trioxide,
bortizomib
,trustozomab,
cetuxmab,
gifitinib,
Erlotinib,
imatinib
mesylste
Erastin
and
analoges ,
sulpha-
salazine,
G , sora-
fenib,
artesunate
,
acetamino
phen ;
RAS-
selective
lethal 3
(RSL3)
Cell death
legend, e.g.
TNF-a,
FasL, or
TRAIL;
microbial
infections;
Ischemic
injury.
DAMPs;
infections;
disturbed
extra-
cellular /
intra-cellu-
lar
homeost-
asis
depends on
MLKL
,RIPK3
Accidental,
Always
Pathologic
al: Severe
stress;
toxic
chemicals,
hypoxia;
heat .

18. Senescence
(Irreversible
Cell arrest)
Regulated/ Programed cell death (RCD/PCD) ACD
Necrosis
Vacules presented Apoptosis Feropto
sis
Immune reactive
Autophagy Paraptosis Necroptosis Pyroptosis
Inhibit
ors
Senolytics
(clear sens-
ecent cells):
Dasatinib,
Quercetin,
azithrom-ycin, ,
navitoclax
Senomorphic
s (SAP
blockers):metf
ormin
resveratrol,Cal
orie
restricition,rap
amycin,
evirolimus
Choroquin,re
sveratrol ,
clarithromyci
n ,quinacrin ,
Epigallocatch
in galeate,3-
methyl
adenine,obato
clax
Actinomy-
cin D and
actinone
Rasagilin,Min
ocyclin,Amifo
stin,adalimum
abinflixmab,
etanerecept,
nicotinamide,
edaravone,
rapamycin
iron
chelators
(deferoxa
min)
lipid
peroxide-
tion
inhibitors
(ferrostati
n, lipr -
oxstatin,
zile-uton
);vita-
min E;G;
alogliptin
vildaglipt
in .
Necrostatin
Ponatinib ,
pazopanib,h
ydroxyaniso
le,necrosulf
onamide
Caspase-1
inhibitors;
glybencla
mide,orido
nin
(NLRP3inf
lammasom
e);
-------------
------

19. A summary of cellular stress responses (e.g. scencence, autophagy ,apoptosis,feroptosis and
necrosis) and health state
Abreviations: AMPK: Adenosine Monophosphate activated Kinase;; AIF:,apoptosis-inducing factor; Atg :autophagy-related genes (Atg) .Apaf-1: Apoptotic protease
activating factor 1; BAD: The BCL2 associated agonist of cell death,;Bcl-2: B-cell lymphoma ; bid :BH3 interacting domain death agonist; Bax: Bcl-2-associated X protein
;CV: cardiovascular; IL: Interleukin;mTOR: mammalian target or mechanistic target of rapamycin complex; ;p53:suppressor
protein ; p21 :cyclin-dependent kinase inhibitor ; ROS :Reactive oxygen species; PUMA:The p53 upregulated modulator of apoptosis ; SIRT1: Sirtuin type 1 ; DOTED
BOXES AND ARROWS = Beneficial pathway

20. Algorythm summary of
cellular stress responses (e.g.
scencence, autophagy and
apoptosis ) and health state in
addition to potential anti-aging
strategy e.g. senolytics and
senomorphics
Abreviations: AMPK: Adenosine
Monophosphate activated Kinase; Atg:
autophagy-related genes; AIF:,apoptosis-
inducing factor;Apaf-1:Apoptotic
protease activating factor 1; BAD: The
BCL2 associated agonist of cell
death,;Bcl-2: B-cell lymphoma ; bid :BH3
interacting domain death agonist; Bax:
Bcl-2-associated X protein ;mTOR:
mammalian target or mechanistic target
of rapamycin complex; Noxa: pro-
apoptotic factor ;p53: tumor suppressor
protein ;p21 :cyclin-dependent kinase
inhibitor (down-regulation of known
p53-repression targets); ROS :Reactive
oxygen species; PUMA:The p53
upregulated modulator of apoptosis ;
SIRT

21. Some promising Senomorphic anti-aging drugs.
agents Target Major effects Clinical trials (CT) Side effects
Calorie
restriction
(without
malnourishing
the individual)
*↑AMP K ,
sirtuins
*↓ 1IGF-1)
signaling ;
(mTOR)
↑ Lifespan by 30-50&↓
risk factors for disease in
humans.
CALERIE (Comprehensive Assessment of the Long-Term Effects of
Reducing Intake of Energy); ClinicalTrials.gov identifier: , protecting
against the development of obesity, cardiovascular disease,
hypertension, and Cancer
Not reported
Metformin
(+ Calorie
Restriction
mimetics)
↑AMPK; SIRT1.
↓mTOR;
antioxidant,
Mitochondria
respiration
Antioxidant, anti-
inflamm-atory, anti-
cancer, anti-atherogenic,
Life extension.
Approved for type II diabetes/ T2D;↑ lifespan in human patients with
diabetes & ↓ risk of Cancer; CT in head & neck squamous cell
carcinoma Phase 2 , prostate cancer phase2 / breast cancer Phase II ;
Fanconi Anemia,phase 1
Anti-aging CT: Phase 2 complete ,. TAME trial ( effects in individuals
(for aging) without diabetes. Phase IV .
Lactic acidosis
Diarrhea Nausea
Vomiting Flatulence
Valproic acid ↓Akt/mTOR,
Oxidative stress;
↑Autophagy
Antiseizure , manic phase
of bipolar disorder,
prevent migraine
headaches
↑ Life span experimentally. No reported clinical trials. , back pain ,diarrhea
Constipation, ,
agitation,
Rapamycin(+
Calorie
Restrictn
mimetic)
mTOR;
Autophagy
induction
Geroprotective. Anti-
oxidant, anti-
inflammatory, anti-
cancer, neuroprotective
CVD (phase 3) Tuberous sclerosis (phase 3) Cancers (phases 1/2/3/4);
Approved for immune-suppression / Clinical trials for Cancer (Phase
I for liver cancer for neuroendocrine tumors.Anti-aging: Phase I trial
completed; phase II trial ongoing
↓immune system,
hepato -toxicity
insulin resistance
Evirolim-us+
(RAD001)
Mechanistic target
of rapamycin
kinasemmT
Immunosuppre-ssion.
antiaging
clinical trials for Cancer (Phase 1,2 for liver cancer/), Phase 2 for
glioma and astrocytoma / for head and neck squamous cell carcinoma
/ for adenoid cystic Cancer
 Mouth sores,
.rash itching
dry skin
fatigue,
diarrhea
edema.
Resvera-
trol +
(polyphenol)
↑Sirutin, p53,
PI3K; AMPK
,Antio xidant ;
proteindeac-etyla
tion;
↑ life span rodents &
non-human primates but
mixed results in humans
;↑autophagy
generally recognized as safe (GRAS) GRAS by FDA; AD (phase
3);Several beneficial effects in phase ii clinical trials against age related
diseases
Intestinal upset
Nausea
perfosin ↓Akt , mTOR
axis,
↑autophagy
Weak anti-cancer. Anti-
telomerase,
Phase 2 trial for metastatic colon cancer → doubled the time to
progression.
Fatigue,↑transaminas
es,gastrointestinal
upset .

22. Some promising Senolytics anti-aging drugs.
drug Target or process Major effects Clinical trials (CT) References
Dasatini
b
Pan‐receptor tyrosine
kinases SCAP =
Dependence
Receptor/Src
Kinase/Tyrosine Kinase
increased lifespan, anti-
cancer,
melanoma/ lymphoma Phase 2;
advanced cancers ,Phase 1 ;
leukemia/ myeloma Phase3;
chronic kidney disease Phase 2 .
Cavalcante et al,2020;
Hickson et al.,2019;
Kim and Kim ,2019;
Pereira eta,2019; Ming et
al.,2018; Childs et
al.,2017.
Querceti
n
Lipoprotein lipase
(LPL) , potassium
voltage-gated channel
subfamily E regul-atory
subunit 2; Bcl-2, p53
/p21 & PI3K/AKT, ,
SIRT1
D+ Q: *↓Atherosclerosis,
Osteoporosis, Hepatic
steatosis & Pulmonary
fibrosis.
*↑Exercise capacity,
Vasom-otor/ Cardiac
function, lifespan
Phase 2 for chronic kidney
disease GRAS by FDA T2D /
CVD (phase 1)
D+Q: chronic kidney disease,
idiopathic pulmonary fibrosis,
hematopoietic stem cell
transplantation.
Okada and Okada,2020;
Hickson et al., 2019; Kim
and Kim,2019; Ming et
al.,2018; Childs et
al.,2017.
Navito-
clax(AB
T 263)
Bcl-2 family (Bcl-2,
BCL-XL, Bcl-W), BH3
mimetics
↑Hair follicle stem cell
function, ↓IR-induced lung
injury.But have platelet
toxicity
leukemia and lymphoma phase 2;
solid tumors 1,2; lung cancer,
phase 1 , ovarian cancer , phase
1
González-Gualda et al.
,2020 ;Childs et al , 2016
;Chang et al.,2016 ;
Childs et al. ,2017;
FOXO4-
DRI
peptide
p53/p21/serpine,
FOXO4-p53 interaction
inhibition
↓Liver toxicity of
doxorubicin ↓Frailty ,↑Hair
growth,renal function
preclinical Kim and Kim,2019;
Baar et al.,2017,
Childs et al.,2017

23. some promising autophagy enhancer antiaging drugs .
drug Target or process Major effects Clinical trials side effects References
Statins Hydroxy-methyl-
glutaryl-CoA reductase,
autophagy induction,
restore telomere length.
Anti-dyslipidemic;
cardio-vascular
protection, neuro-
protection,antiinflamm -
atory ,anti-cancerous
Hypercholesterolemia (FDA-approved),
CVD (phase 4 Myocardial infarction
(phase 4), Sexual dysfunction (phase 4)
T2D (phase 4) Schizophrenia (phase 4)
Headache depression
sleepiness dizziness,
diarrhea memory loss,
diabetes
Jahn et al.,2020,
Blagosklonny.2017,
Belchamber and Donnelly,
2017; Boccardi et al.,2013,
Mehta et al.,2006
Aspirin ↓COX-1, COX-2, ;
autophagy induction)
↑ life span in animals,
CV protection, anti-
atherogenic.
T2D (phase 3/4) Heart disease (phase
3/4) Atherosclerosis (phase 4),cancers
(phases 1-4 ),Obesity (phase 1)
Diarrhea, headache, loss
of appetite, vomiting,
↑weight
Piskovatska etal,
2019 ; Danilov et
al.,2015; Wan et
al,2013.
Melatonin
(biogenic-amine)
Autophagy induction,
Melatonin receptor
(MT1, MT2 (on the cell
membrane) GPR50
Antioxidant, immune-
modulatory, antipro-
lifera-tive& endocrine
modulator, antiinflam -
matory, anticancerous ,
life extension
GRAS by FDA Cancers (phases 1/2/3/4)
Glucose tolerance (phase 3) Insomnia
(phase 2) T2D (phase 2)
Alzheimer's disease (phase 2)
Headache depression
sleepiness dizziness
irritability
Jauhari etal,2020;
Reiter etal,2018;
Majidinia etal,2018;
Emet etal.,2016 ;
Hardeland ,2013
Epigallocatechin
gallate
Bcl2, NOS2, LamR,
EGFR, Telomerase,
Topoisomerase II,
DNMT1
Antioxidant, antiinfla-
mmatory, anticancer ,
antiatherogenic ,life
extension
generally recognized as safe (GRAS) by
FDA,: A.D. (phase 2/3)
nervous sness, vomiting ,
diarrhea , Irritability,
arrhythmia
Kumar et al.,2020 ;Si et al.
,2019; Zhang et al.,2019;
Huang and Liu,2017.
Spermi-dine Autophagy
induction, ↓ HA &↓
acetyl transferase
activity of E1A-
associated protein
p300
Protein
deacetylation,
antioxidant
,antinflammatory
,neuroprotective
,life extension.
Anti-aging trials: Observation
trial Complete ; Phase 2 clinical
trial ongoing
Not reported in
human
Xu etal,2020; Wang
etal,2020;Nilsson
and Persson, 2019;
Madeo et al.,2018;
Minois, 2014;
Curcumin
(polyphenol)
Calories restriction
mimetics,
Autophagy
induction,senolytic,
senomorphic,
↑lifespan, ↓ age-
related diseases,
e.g., athero-
sclerosis
Antioxidant,
antiinflammatory,
anticancer, , wound
healing and
↑memory,
generally recognized as safe
(GRAS) by FDA
Alzheimer's disease: A.D. (phase
2), Cancer (phase 2)
Flatulence Nausea
Diarrhea
Stępień et al.,2020;
Bielak-Zmijewska et
al.,2019; Shailaja et
al.,2017; Sikora et
al.,2010

24. THANK YOU