License, which permits unrestricted use, distribution, and reproduction in any medium, provided t... more License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Stress resistance capacity is a hallmark of longevity protection and survival throughout the plant and animal kingdoms. Latent pathway activation of protective cascades, triggered by environmental challenges to tolerate heat, oxygen deprivation, reactive oxygen species (ROS), diet restriction, and exercise provides tolerance to these stresses. Age-related changes and disease vulnerability mark an increase in damage, like damage induced by environmental challenges. An alternative approach to immunotherapy intervention in Alzheimer’s Disease is the use of mimetics of stress to upregulate endogenous protective cascades to repair age damage, shift the balance of apoptosis to regeneration to promote delay of onset, and even progression of Alzheimer’s disease memory dysfunction. Mimetics of environmental stress, hormetic agents, and triggers, endogenous or e...
In ciliates there are examples of cells which have different proliferation potential in the macro... more In ciliates there are examples of cells which have different proliferation potential in the macronucleus. Those species with limited macronuclear proliferation potential require sex to activate the reserve nucleus. In terms of the capital investment theory, some ciliates invested in their spare nucleus without loss of their original potential, while others accumulated debts and needed the reserve account to maintain life. Other cells neglected maintenance of their reserve account and failed unless their venture capital account was not a self-sustaining venture. Sex provided access to the reserve account and had to occur before deterioration of the reserve account. The question is not when cellular immortality was lost, but rather when immortality was partitioned from a mortal segment. The separation provided the option both for senescence and evolution in multicellular organisms. In colonial flagellates, separation of cells with infinite and finite cell lifespan potential occurred in some species, while in others the separation did not involve loss of immortality. In colonial flagellates, sex did not become an obligate stage. The immortal cells are haploid and could not accumulate damage and live (in contrast with the diploids in the ciliated protozoans). The present theory predicts that differences between species or cells with infinite versus finite lifespan potential may reveal differences in the critical determinants of longevity. Senescence could arise as an accident, as well as a design of nuclear differentiation. Cells therefore may have a much greater reserve for totipotency than would be predicted if they were assumed to lose immortality simply by the act of differentiation.
American Journal of Pharmacology and Toxicology, 2008
Hormesis refers to the ability of a chemical or physical agent to condition the physiological sta... more Hormesis refers to the ability of a chemical or physical agent to condition the physiological state of an organism to tolerate stress with low doses of otherwise harmful agents. Evolutionary evidence shows that the survival and longevity of species hinge on their optimal ability to resist stress challenge. Hormesis is a potent strategy to stimulate latent repair processes to tolerate a specific challenge. Examples of hormetic agent-mimetics, which induce at least partial physiological conditioning, activate known pathways of longevity determinants, i.e., genetic stability, altered metabolism, immunoregulation and stress resistance. Despite the diversity of age-related diseases, glucose and oxidation-mediated protein and DNA damage are common denominators. The associated physiological conditioning-benefits may trigger: 1) activation of latent stress resistance pathways of youthful DNA repair; 2) increased resistance to oxidizing pollutants; 3) improved protein structure and function; 4) improved immunity; 5) damaged tissue remodeling; 6) adjustments in central and peripheral nervous systems; 7) altered metabolism; and 8) delay or breaking of inappropriate protein cross-links. Hormetic mimetics have intervention potential in cancer, diabetes, age-related diseases, infectious diseases, heart and kidney failure, cardiovascular diseases and Alzheimer's disease. Small nucleotide SOS signals, dipeptides, ethanol, thiols, and metals and conserved peptide sequences found in sharks, frogs, woodchucks, and bears, can regulate cytokines, cellular immunity, and central and peripheral neuronal regulatory pathways to promote healthy blood pressure maintenance, heart rate, and metabolic pathways. disease sensitivity. Conserved stress mimetics are highlighted here that rejuvenate DNA and proteins repair and thus may intervene in aging, disease, and trauma. Hibernation Induction Trigger mimetics, Deltorphins, emerge as novel hormetic agents, effective both as pre and post exposure to physiological conditioners to tolerate stress, and prevent damage, and delay possibly aging. Hormesis mimetics offer powerful survival strategies, with better control over the beneficial dose response. Combinations of several mimetics may more closely mimic environmental challenges, which stimulate multiple stress responses.
This study tests the hypothesis that pretreatment and/or posttreatment with 5-aminoimidazole-4car... more This study tests the hypothesis that pretreatment and/or posttreatment with 5-aminoimidazole-4carboxamide ribonucleoside (AICAR), an inducer of adenosine monophosphateYactivated protein, will extend the golden hour of survival time in rats subjected to severe hemorrhagic shock in the absence of available fluid resuscitation. Three days before hemorrhage, at 24-h intervals, animals were given three i.p. injections of AICAR (pretreatment) or saline (control/posttreatment). At the end of hemorrhage, animals (control/pretreatment) received a single i.v. injection of saline, whereas the posttreatment group received a single i.v. injection of AICAR (posttreatment). All treatment groups received the same total volume of fluid both before and immediately after hemorrhage. Both AICAR treatment groups had significantly(P G 0.01) extended survival time during the decompensatory phase of shock when compared with saline control group, pretreatment: 324 T 21 min; posttreatment: 187 T 16 min; and saline: 55 T 10 min. Heart rate was significantly (P G 0.01) decreased following hemorrhage for pretreatment animals versus saline controls, 237 T 16 vs. 312 T 33 beats/min, respectively. Heart rate for both the pretreatment and posttreatment animals was also significantly (P G 0.01) lower after 30 min versus saline control group, pretreatment: 247 T 13 beats/min; posttreatment: 240 T 20 beats/min; saline: 415 T 18 beats/min. Lactate levels were also significantly reduced 6.3 T 0.71 mmol/L (pretreatment), 7.1 T 0.47 mmol/L (posttreatment), 8.9 T 0.21 mmol/L (saline). The improvement in hemodynamic stability is reflected in the significant increase in the golden-hour survival time in animals subjected to severe hemorrhagic shock.
International Journal of Alzheimer's Disease, 2012
Stress resistance capacity is a hallmark of longevity protection and survival throughout the plan... more Stress resistance capacity is a hallmark of longevity protection and survival throughout the plant and animal kingdoms. Latent pathway activation of protective cascades, triggered by environmental challenges to tolerate heat, oxygen deprivation, reactive oxygen species (ROS), diet restriction, and exercise provides tolerance to these stresses. Age-related changes and disease vulnerability mark an increase in damage, like damage induced by environmental challenges. An alternative approach to immunotherapy intervention in Alzheimer's Disease is the use of mimetics of stress to upregulate endogenous protective cascades to repair age damage, shift the balance of apoptosis to regeneration to promote delay of onset, and even progression of Alzheimer's disease memory dysfunction. Mimetics of environmental stress, hormetic agents, and triggers, endogenous or engineered, can "trick" activation of expression patterns of repair and rejuvenation. Examples of known candidate triggers of heat response, endogenous antioxidants, DNA repair, exercise, hibernation, and telomeres are available for AD intervention trials. Telomeres and telomerase emerge as major regulators in crossroads of senescence, cancer, and rejuvenation responsive to mimetics of telomeres. Lessons emerge from transgenic rodent models, the long-lived mole rat, clinical studies, and conserved innate pathways of stress resistance. Cross-reaction of benefits of different triggers promises intervention into seemingly otherwise unrelated diseases.
Senescence is characterized by the decline in the ability to cope with stress. Hormesis regulatio... more Senescence is characterized by the decline in the ability to cope with stress. Hormesis regulation of opposing biological effects of low and high dosages, can determine longevity, and disease vulnerability at appropriate doses. Regulation of age-related changes in micro RNA opens new areas of therapeutic targets. Micro RNA downregulates stress response pathways with age establishing vulnerability to multiple age related disease which, if targeted could theoretically delay senescence. Mitochondrial targeted drugs have intervened in seemingly otherwise unrelated pathologies like neurological diseases, Alzheimer's disease, infections, diabetes, acute ischemic shock, and wound healing; an example of a common magic bullet for intervention in mitochondrial dysfunction pathologies of oxidative stress. The telomerase subunit, TERT, the promiscuous reverse transcriptase, exhibits hormetic activity, benefit at low levels, dysfunctional at high levels, and is required for signally survival. The appropriate targeted telomerase therapy is key for optimal desired drug therapy for inhibition in cancer and HIV infected therapy and enhanced in bystander cells for oxidative stress tolerance. Comparative biology studies reveal the role of Neuregulin and Nrf2, as key players in the puzzle of the long lived disease free mole rat despite high levels of oxidative stress. A hibernation stress response cold shock peptide restores synaptic plasticity, and is beneficial in neurodegeneration. Muscles and gut are not only responsible for their respective roles in locomotion and digestion but also regulate systemic responses in the body. New insights into the roles of muscles and gut change how drugs affect multiple organs and impact the route of administration. While oxidative stress can either signal metabolic benefits, death or be neutralized by a wheelhouse of antioxidant pathways, recent technological advances and conceptual shifts, allow regulation of opposing consequences by appropriate targeting of drugs to achieve protective effects in multiple age related diseases.
Annals of the New York Academy of Sciences, Dec 1, 2005
Hormesis is an adaptive response to low doses of otherwise harmful agents by triggering a cascade... more Hormesis is an adaptive response to low doses of otherwise harmful agents by triggering a cascade of stress-specific resistance pathways. Evidence from protozoa, nematodes, flies, rodents, and primates indicate that stress-induced tolerance modulates survival and longevity. "Reality" is that hormesis can prolong the healthy life span. Genetic background provides the potential for longevity duration induced by stress. Senesence, or aging, is generally thought to be due to a different impact of selection for alleles positive for reproduction during early life but harmful in later life, a process called antagonistic pleiotropy (multiple phenotypic changes by a single gene). After reproduction, life span is "invisible" to selection. I propose the revision that mutations selected for survival until reproduction in early life may also extend later life (protagonistic pleiotropy). The protagonist candidate genes for extended life span are hormetic response genes, which activate the protective effect in both early and later life. My revision of the earlier evolutionary theory implies that natural selection of genes critical for early survival (life span until reproduction) can also be beneficial for extended longevity in old age, tipping the evolutionary balance in favor of a latent inducible life span extension unless excess stressor challenge exceeds the protection capacity. Mimetic triggers of the stress response promise the option of tricking the induction of metabolic pathways that confer resistance to environmental challenges, increased healthy life span, rejuvenation, and disease intervention without the danger of overwhelming damage by the stressor. Public policy should anticipate an increase in healthy life span.
Deltorphin E was investigated as a pharmaceutical intervention in the ischemic hemorrhagic model.... more Deltorphin E was investigated as a pharmaceutical intervention in the ischemic hemorrhagic model. To monitor the hemodynamic biomarkers mean arterial pressure (MAP) and heart rate (HR) and to facilitate i.v. injections, rats were surgically fitted with femoral artery and vein catheters under anesthesia. After removal of 48% of total blood volume (range, 12-15 mL), posthemorrhage i.v. injections of 5.5-mg/kg deltorphin E were found to significantly (P < 0.05) increase maximum MAP, pulse pressure, and survival after hemorrhage, whereas lactic acid concentration was decreased when compared with saline injections. The results for the 5.5-mg/kg deltorphin E-treated animals versus saline controls showed the following values (expressed as mean ± SEM): maximum MAP, 58 ± 7 vs. 35 ± 9 mmHg, respectively; lactic acid, 6.5 ± 1.25 vs. 8.9 ± 0.12 mmol/L, respectively; pulse pressure, 47.9 ± 0.55 vs. 38.3 ± 0.44 mmHg, respectively; and at least a fourfold increase in survival, 331 ± 18 vs. 50 ± 8 min, respectively. Heart rate in deltorphin E-treated groups was not significantly different from that in saline-treated groups (maximum HR, 396 ± 40 vs. 425 ± 94 bpm, respectively). Using logistic analysis, deltorphin E did not significantly alter the baroreflex sensitivity. However, a significant deltorphin E dose-dependent correlation was found between survival time and lactic acid production. Increased pulse pressure was also correlated with survival. Glibenclamide, a potassium-sensitive adenosine triphosphate-sensitive channel blocker, did not interfere with the positive effects of deltorphin E. Only the antagonists tested, known to affect &dgr;2-opioid receptors, interfered with the deltorphin E survival benefit after hemorrhage. As a conclusion, deltorphin E is an effective pharmaceutical intervention in severe hemorrhagic shock and, perhaps, in other ischemic shock scenarios when administered after the onset of stress. Therefore, deltorphin E may have clinical potential.
Aged cells have significantly fewer food vacuoles and ingest fewer bacteria than young cells. Los... more Aged cells have significantly fewer food vacuoles and ingest fewer bacteria than young cells. Loss of food vacuoles was explained by a decreasing difference in the food vacuole formation and excretion rates; the formation rate declined more rapidly than the excretion rate, approaching equivalence at 160 fissions, when the proportion of cells with no food vacuoles, in the presence of excess food, abruptly increased. A model for cellular aging is presented in which control of organelle numbers and cyclical interactions between the nucleus and cytoplasm may be of critical importance.
The effect of specific pulsating currents on Paramecia longevity was monitored using electromagne... more The effect of specific pulsating currents on Paramecia longevity was monitored using electromagnetic current induction. Paramecium consists of eukaryotic cells with a surface membrane which exhibits ionic mechanisms of excitation similar to muscle and nerve cells of metazoans. These protozoan cells can generate receptor and action potentials in response to proper electrical, mechanical or chemical stimuli. Paramecium has also been used as a clonal aging system and as a model system of cellular senescence since the number of cell divisions after origin of the clone at fertilization until the death is limited, predictable, short, and species-specific. When cells were cultivated in pulsating currents, the survival of treated cells was increased relative to controls at specific age intervals in response to specific current signals. The induced voltage was obtained using air-gap coils driven by a programmable supply. The basic pulse-waveform and the periodicity (single pulse versus pulse burst and repetition rate) were examined. The results show that a significant (P < 0.05) mean lifespan could be attained with certain signals. When cells were shifted to optimal current signals for given ages, a 17 % increase in mean lifespan was obtained. Maximal lifespan could be increased 33 S by exposure to an optimal program of specific current signals.
Ten ART-naive patients with a complete GIT sample set were selected for genetic studies. Th ree p... more Ten ART-naive patients with a complete GIT sample set were selected for genetic studies. Th ree patients, HIV019, HIV021 and HIV029, who had suffi cient sample were selected for extensive phylogenetic analysis of HIV-1 RNA quasispecies. Th ese patients were recruited at the Comprehensive Care, Management and Treatment Clinic in Pretoria as part of a previously described study
... Journal of Proto-zoology, 1955, 2, 7. Dryl, S. Antigenie transformation in Paramecium aurelia... more ... Journal of Proto-zoology, 1955, 2, 7. Dryl, S. Antigenie transformation in Paramecium aurelia after homologous antiserum treatment during autogamy and conjugation. ... Kimball, RF, Gaither, N., &amp;amp;amp; Perdue, SW Meta-bolic repair of premutational damage in Para-mecium. ...
A search was undertaken for naturally occurring genetic markers for use in clonal aging studies o... more A search was undertaken for naturally occurring genetic markers for use in clonal aging studies of Paramecium tetraurelia. Clonal age is defined as the number of cell divisions since the last sexual process. Autogamy (self-fertilization) is a sexual process which can occur in aging lines, resulting in homozygosity and initiation of the next generation. Such &quot;illicit&quot; autogamies must be detected and eliminated from the aged clone. With codominant alleles, heterozygous aging lines can be established which will express a phenotype distinguishable from that of either parental type and autogamy can then be monitored by the appearance of either segregant homozygous phenotype. However, very few codominant alleles are available in this species. Electrophoretic mobilities of malic dehydrogenase (MDH) were assayed in 11 stocks of Paramecium tetraurelia by polyacrylamide gel electrophoresis. Nine stocks showed a single-banded &quot;stock 51&quot; type, while stock 174 and stock 29 each exhibited unique mobility. Crosses between stock 51 and the deviant stocks revealed distinct three-banded patterns indicative of heterozygosity of the F1 generation. In the autogamous F2 generation, 1:1 segregation of the parental types were recovered. The pattern of inheritance is consistent with codominant alleles and Mendelian inheritance. These naturally occurring biochemical markers are stable with increasing clonal age and are therefore useful genetic markers for studies of cellular aging.
The use of the established mutagenesis assay in Paramecium as a prescreen for hazardous environme... more The use of the established mutagenesis assay in Paramecium as a prescreen for hazardous environmental particles is described. Since these protozoans ingest particles of the size respired by animals and man, the biological effects of the respirable fraction of fly ash particles were monitored in particle-feeding eukaryotic cells. Fly ash from coal combustion was utilized for these studies and was found to be mutagenic. The effects of physical and chemical treatment of the particle mutagenicity provided evidence for both heat-stable, heat-labile and acid extractable mutagenic agents.
License, which permits unrestricted use, distribution, and reproduction in any medium, provided t... more License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Stress resistance capacity is a hallmark of longevity protection and survival throughout the plant and animal kingdoms. Latent pathway activation of protective cascades, triggered by environmental challenges to tolerate heat, oxygen deprivation, reactive oxygen species (ROS), diet restriction, and exercise provides tolerance to these stresses. Age-related changes and disease vulnerability mark an increase in damage, like damage induced by environmental challenges. An alternative approach to immunotherapy intervention in Alzheimer’s Disease is the use of mimetics of stress to upregulate endogenous protective cascades to repair age damage, shift the balance of apoptosis to regeneration to promote delay of onset, and even progression of Alzheimer’s disease memory dysfunction. Mimetics of environmental stress, hormetic agents, and triggers, endogenous or e...
In ciliates there are examples of cells which have different proliferation potential in the macro... more In ciliates there are examples of cells which have different proliferation potential in the macronucleus. Those species with limited macronuclear proliferation potential require sex to activate the reserve nucleus. In terms of the capital investment theory, some ciliates invested in their spare nucleus without loss of their original potential, while others accumulated debts and needed the reserve account to maintain life. Other cells neglected maintenance of their reserve account and failed unless their venture capital account was not a self-sustaining venture. Sex provided access to the reserve account and had to occur before deterioration of the reserve account. The question is not when cellular immortality was lost, but rather when immortality was partitioned from a mortal segment. The separation provided the option both for senescence and evolution in multicellular organisms. In colonial flagellates, separation of cells with infinite and finite cell lifespan potential occurred in some species, while in others the separation did not involve loss of immortality. In colonial flagellates, sex did not become an obligate stage. The immortal cells are haploid and could not accumulate damage and live (in contrast with the diploids in the ciliated protozoans). The present theory predicts that differences between species or cells with infinite versus finite lifespan potential may reveal differences in the critical determinants of longevity. Senescence could arise as an accident, as well as a design of nuclear differentiation. Cells therefore may have a much greater reserve for totipotency than would be predicted if they were assumed to lose immortality simply by the act of differentiation.
American Journal of Pharmacology and Toxicology, 2008
Hormesis refers to the ability of a chemical or physical agent to condition the physiological sta... more Hormesis refers to the ability of a chemical or physical agent to condition the physiological state of an organism to tolerate stress with low doses of otherwise harmful agents. Evolutionary evidence shows that the survival and longevity of species hinge on their optimal ability to resist stress challenge. Hormesis is a potent strategy to stimulate latent repair processes to tolerate a specific challenge. Examples of hormetic agent-mimetics, which induce at least partial physiological conditioning, activate known pathways of longevity determinants, i.e., genetic stability, altered metabolism, immunoregulation and stress resistance. Despite the diversity of age-related diseases, glucose and oxidation-mediated protein and DNA damage are common denominators. The associated physiological conditioning-benefits may trigger: 1) activation of latent stress resistance pathways of youthful DNA repair; 2) increased resistance to oxidizing pollutants; 3) improved protein structure and function; 4) improved immunity; 5) damaged tissue remodeling; 6) adjustments in central and peripheral nervous systems; 7) altered metabolism; and 8) delay or breaking of inappropriate protein cross-links. Hormetic mimetics have intervention potential in cancer, diabetes, age-related diseases, infectious diseases, heart and kidney failure, cardiovascular diseases and Alzheimer's disease. Small nucleotide SOS signals, dipeptides, ethanol, thiols, and metals and conserved peptide sequences found in sharks, frogs, woodchucks, and bears, can regulate cytokines, cellular immunity, and central and peripheral neuronal regulatory pathways to promote healthy blood pressure maintenance, heart rate, and metabolic pathways. disease sensitivity. Conserved stress mimetics are highlighted here that rejuvenate DNA and proteins repair and thus may intervene in aging, disease, and trauma. Hibernation Induction Trigger mimetics, Deltorphins, emerge as novel hormetic agents, effective both as pre and post exposure to physiological conditioners to tolerate stress, and prevent damage, and delay possibly aging. Hormesis mimetics offer powerful survival strategies, with better control over the beneficial dose response. Combinations of several mimetics may more closely mimic environmental challenges, which stimulate multiple stress responses.
This study tests the hypothesis that pretreatment and/or posttreatment with 5-aminoimidazole-4car... more This study tests the hypothesis that pretreatment and/or posttreatment with 5-aminoimidazole-4carboxamide ribonucleoside (AICAR), an inducer of adenosine monophosphateYactivated protein, will extend the golden hour of survival time in rats subjected to severe hemorrhagic shock in the absence of available fluid resuscitation. Three days before hemorrhage, at 24-h intervals, animals were given three i.p. injections of AICAR (pretreatment) or saline (control/posttreatment). At the end of hemorrhage, animals (control/pretreatment) received a single i.v. injection of saline, whereas the posttreatment group received a single i.v. injection of AICAR (posttreatment). All treatment groups received the same total volume of fluid both before and immediately after hemorrhage. Both AICAR treatment groups had significantly(P G 0.01) extended survival time during the decompensatory phase of shock when compared with saline control group, pretreatment: 324 T 21 min; posttreatment: 187 T 16 min; and saline: 55 T 10 min. Heart rate was significantly (P G 0.01) decreased following hemorrhage for pretreatment animals versus saline controls, 237 T 16 vs. 312 T 33 beats/min, respectively. Heart rate for both the pretreatment and posttreatment animals was also significantly (P G 0.01) lower after 30 min versus saline control group, pretreatment: 247 T 13 beats/min; posttreatment: 240 T 20 beats/min; saline: 415 T 18 beats/min. Lactate levels were also significantly reduced 6.3 T 0.71 mmol/L (pretreatment), 7.1 T 0.47 mmol/L (posttreatment), 8.9 T 0.21 mmol/L (saline). The improvement in hemodynamic stability is reflected in the significant increase in the golden-hour survival time in animals subjected to severe hemorrhagic shock.
International Journal of Alzheimer's Disease, 2012
Stress resistance capacity is a hallmark of longevity protection and survival throughout the plan... more Stress resistance capacity is a hallmark of longevity protection and survival throughout the plant and animal kingdoms. Latent pathway activation of protective cascades, triggered by environmental challenges to tolerate heat, oxygen deprivation, reactive oxygen species (ROS), diet restriction, and exercise provides tolerance to these stresses. Age-related changes and disease vulnerability mark an increase in damage, like damage induced by environmental challenges. An alternative approach to immunotherapy intervention in Alzheimer's Disease is the use of mimetics of stress to upregulate endogenous protective cascades to repair age damage, shift the balance of apoptosis to regeneration to promote delay of onset, and even progression of Alzheimer's disease memory dysfunction. Mimetics of environmental stress, hormetic agents, and triggers, endogenous or engineered, can "trick" activation of expression patterns of repair and rejuvenation. Examples of known candidate triggers of heat response, endogenous antioxidants, DNA repair, exercise, hibernation, and telomeres are available for AD intervention trials. Telomeres and telomerase emerge as major regulators in crossroads of senescence, cancer, and rejuvenation responsive to mimetics of telomeres. Lessons emerge from transgenic rodent models, the long-lived mole rat, clinical studies, and conserved innate pathways of stress resistance. Cross-reaction of benefits of different triggers promises intervention into seemingly otherwise unrelated diseases.
Senescence is characterized by the decline in the ability to cope with stress. Hormesis regulatio... more Senescence is characterized by the decline in the ability to cope with stress. Hormesis regulation of opposing biological effects of low and high dosages, can determine longevity, and disease vulnerability at appropriate doses. Regulation of age-related changes in micro RNA opens new areas of therapeutic targets. Micro RNA downregulates stress response pathways with age establishing vulnerability to multiple age related disease which, if targeted could theoretically delay senescence. Mitochondrial targeted drugs have intervened in seemingly otherwise unrelated pathologies like neurological diseases, Alzheimer's disease, infections, diabetes, acute ischemic shock, and wound healing; an example of a common magic bullet for intervention in mitochondrial dysfunction pathologies of oxidative stress. The telomerase subunit, TERT, the promiscuous reverse transcriptase, exhibits hormetic activity, benefit at low levels, dysfunctional at high levels, and is required for signally survival. The appropriate targeted telomerase therapy is key for optimal desired drug therapy for inhibition in cancer and HIV infected therapy and enhanced in bystander cells for oxidative stress tolerance. Comparative biology studies reveal the role of Neuregulin and Nrf2, as key players in the puzzle of the long lived disease free mole rat despite high levels of oxidative stress. A hibernation stress response cold shock peptide restores synaptic plasticity, and is beneficial in neurodegeneration. Muscles and gut are not only responsible for their respective roles in locomotion and digestion but also regulate systemic responses in the body. New insights into the roles of muscles and gut change how drugs affect multiple organs and impact the route of administration. While oxidative stress can either signal metabolic benefits, death or be neutralized by a wheelhouse of antioxidant pathways, recent technological advances and conceptual shifts, allow regulation of opposing consequences by appropriate targeting of drugs to achieve protective effects in multiple age related diseases.
Annals of the New York Academy of Sciences, Dec 1, 2005
Hormesis is an adaptive response to low doses of otherwise harmful agents by triggering a cascade... more Hormesis is an adaptive response to low doses of otherwise harmful agents by triggering a cascade of stress-specific resistance pathways. Evidence from protozoa, nematodes, flies, rodents, and primates indicate that stress-induced tolerance modulates survival and longevity. &quot;Reality&quot; is that hormesis can prolong the healthy life span. Genetic background provides the potential for longevity duration induced by stress. Senesence, or aging, is generally thought to be due to a different impact of selection for alleles positive for reproduction during early life but harmful in later life, a process called antagonistic pleiotropy (multiple phenotypic changes by a single gene). After reproduction, life span is &quot;invisible&quot; to selection. I propose the revision that mutations selected for survival until reproduction in early life may also extend later life (protagonistic pleiotropy). The protagonist candidate genes for extended life span are hormetic response genes, which activate the protective effect in both early and later life. My revision of the earlier evolutionary theory implies that natural selection of genes critical for early survival (life span until reproduction) can also be beneficial for extended longevity in old age, tipping the evolutionary balance in favor of a latent inducible life span extension unless excess stressor challenge exceeds the protection capacity. Mimetic triggers of the stress response promise the option of tricking the induction of metabolic pathways that confer resistance to environmental challenges, increased healthy life span, rejuvenation, and disease intervention without the danger of overwhelming damage by the stressor. Public policy should anticipate an increase in healthy life span.
Deltorphin E was investigated as a pharmaceutical intervention in the ischemic hemorrhagic model.... more Deltorphin E was investigated as a pharmaceutical intervention in the ischemic hemorrhagic model. To monitor the hemodynamic biomarkers mean arterial pressure (MAP) and heart rate (HR) and to facilitate i.v. injections, rats were surgically fitted with femoral artery and vein catheters under anesthesia. After removal of 48% of total blood volume (range, 12-15 mL), posthemorrhage i.v. injections of 5.5-mg/kg deltorphin E were found to significantly (P < 0.05) increase maximum MAP, pulse pressure, and survival after hemorrhage, whereas lactic acid concentration was decreased when compared with saline injections. The results for the 5.5-mg/kg deltorphin E-treated animals versus saline controls showed the following values (expressed as mean ± SEM): maximum MAP, 58 ± 7 vs. 35 ± 9 mmHg, respectively; lactic acid, 6.5 ± 1.25 vs. 8.9 ± 0.12 mmol/L, respectively; pulse pressure, 47.9 ± 0.55 vs. 38.3 ± 0.44 mmHg, respectively; and at least a fourfold increase in survival, 331 ± 18 vs. 50 ± 8 min, respectively. Heart rate in deltorphin E-treated groups was not significantly different from that in saline-treated groups (maximum HR, 396 ± 40 vs. 425 ± 94 bpm, respectively). Using logistic analysis, deltorphin E did not significantly alter the baroreflex sensitivity. However, a significant deltorphin E dose-dependent correlation was found between survival time and lactic acid production. Increased pulse pressure was also correlated with survival. Glibenclamide, a potassium-sensitive adenosine triphosphate-sensitive channel blocker, did not interfere with the positive effects of deltorphin E. Only the antagonists tested, known to affect &dgr;2-opioid receptors, interfered with the deltorphin E survival benefit after hemorrhage. As a conclusion, deltorphin E is an effective pharmaceutical intervention in severe hemorrhagic shock and, perhaps, in other ischemic shock scenarios when administered after the onset of stress. Therefore, deltorphin E may have clinical potential.
Aged cells have significantly fewer food vacuoles and ingest fewer bacteria than young cells. Los... more Aged cells have significantly fewer food vacuoles and ingest fewer bacteria than young cells. Loss of food vacuoles was explained by a decreasing difference in the food vacuole formation and excretion rates; the formation rate declined more rapidly than the excretion rate, approaching equivalence at 160 fissions, when the proportion of cells with no food vacuoles, in the presence of excess food, abruptly increased. A model for cellular aging is presented in which control of organelle numbers and cyclical interactions between the nucleus and cytoplasm may be of critical importance.
The effect of specific pulsating currents on Paramecia longevity was monitored using electromagne... more The effect of specific pulsating currents on Paramecia longevity was monitored using electromagnetic current induction. Paramecium consists of eukaryotic cells with a surface membrane which exhibits ionic mechanisms of excitation similar to muscle and nerve cells of metazoans. These protozoan cells can generate receptor and action potentials in response to proper electrical, mechanical or chemical stimuli. Paramecium has also been used as a clonal aging system and as a model system of cellular senescence since the number of cell divisions after origin of the clone at fertilization until the death is limited, predictable, short, and species-specific. When cells were cultivated in pulsating currents, the survival of treated cells was increased relative to controls at specific age intervals in response to specific current signals. The induced voltage was obtained using air-gap coils driven by a programmable supply. The basic pulse-waveform and the periodicity (single pulse versus pulse burst and repetition rate) were examined. The results show that a significant (P < 0.05) mean lifespan could be attained with certain signals. When cells were shifted to optimal current signals for given ages, a 17 % increase in mean lifespan was obtained. Maximal lifespan could be increased 33 S by exposure to an optimal program of specific current signals.
Ten ART-naive patients with a complete GIT sample set were selected for genetic studies. Th ree p... more Ten ART-naive patients with a complete GIT sample set were selected for genetic studies. Th ree patients, HIV019, HIV021 and HIV029, who had suffi cient sample were selected for extensive phylogenetic analysis of HIV-1 RNA quasispecies. Th ese patients were recruited at the Comprehensive Care, Management and Treatment Clinic in Pretoria as part of a previously described study
... Journal of Proto-zoology, 1955, 2, 7. Dryl, S. Antigenie transformation in Paramecium aurelia... more ... Journal of Proto-zoology, 1955, 2, 7. Dryl, S. Antigenie transformation in Paramecium aurelia after homologous antiserum treatment during autogamy and conjugation. ... Kimball, RF, Gaither, N., &amp;amp;amp; Perdue, SW Meta-bolic repair of premutational damage in Para-mecium. ...
A search was undertaken for naturally occurring genetic markers for use in clonal aging studies o... more A search was undertaken for naturally occurring genetic markers for use in clonal aging studies of Paramecium tetraurelia. Clonal age is defined as the number of cell divisions since the last sexual process. Autogamy (self-fertilization) is a sexual process which can occur in aging lines, resulting in homozygosity and initiation of the next generation. Such &quot;illicit&quot; autogamies must be detected and eliminated from the aged clone. With codominant alleles, heterozygous aging lines can be established which will express a phenotype distinguishable from that of either parental type and autogamy can then be monitored by the appearance of either segregant homozygous phenotype. However, very few codominant alleles are available in this species. Electrophoretic mobilities of malic dehydrogenase (MDH) were assayed in 11 stocks of Paramecium tetraurelia by polyacrylamide gel electrophoresis. Nine stocks showed a single-banded &quot;stock 51&quot; type, while stock 174 and stock 29 each exhibited unique mobility. Crosses between stock 51 and the deviant stocks revealed distinct three-banded patterns indicative of heterozygosity of the F1 generation. In the autogamous F2 generation, 1:1 segregation of the parental types were recovered. The pattern of inheritance is consistent with codominant alleles and Mendelian inheritance. These naturally occurring biochemical markers are stable with increasing clonal age and are therefore useful genetic markers for studies of cellular aging.
The use of the established mutagenesis assay in Paramecium as a prescreen for hazardous environme... more The use of the established mutagenesis assay in Paramecium as a prescreen for hazardous environmental particles is described. Since these protozoans ingest particles of the size respired by animals and man, the biological effects of the respirable fraction of fly ash particles were monitored in particle-feeding eukaryotic cells. Fly ash from coal combustion was utilized for these studies and was found to be mutagenic. The effects of physical and chemical treatment of the particle mutagenicity provided evidence for both heat-stable, heat-labile and acid extractable mutagenic agents.
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Papers by Joan Sonneborn