Approaches for extending human healthspan: from antioxidants to healthspan pharmacology

2017 ◽  
Vol 61 (3) ◽  
pp. 389-399 ◽  
Author(s):  
Jan Gruber ◽  
Barry Halliwell
Keyword(s):  
Oxidative Damage ◽  
Relative Importance ◽  
Healthy Individuals ◽  
Human Lifespan ◽  
Preventative Intervention ◽  
Alternative Approach ◽  
Ageing Processes ◽  
Age Dependent ◽  
Intervention Trials ◽  
Independent Chain

Dramatic increases in human lifespan and declining population growth are monumental achievements but these same achievements have also led to many societies today ageing at a faster rate than ever before. Extending healthy lifespan (healthspan) is a key translational challenge in this context. Disease-centric approaches to manage population ageing risk are adding years to life without adding health to these years. The growing consensus that ageing is driven by a limited number of interconnected processes suggests an alternative approach. Instead of viewing each age-dependent disease as the result of an independent chain of events, this approach recognizes that most age-dependent diseases depend on and are driven by a limited set of ageing processes. While the relative importance of each of these processes and the best intervention strategies targeting them are subjects of debate, there is increasing interest in providing preventative intervention options to healthy individuals even before overt age-dependent diseases manifest. Elevated oxidative damage is involved in the pathophysiology of most age-dependent diseases and markers of oxidative damage often increase with age in many organisms. However, correlation is not causation and, sadly, many intervention trials of supposed antioxidants have failed to extend healthspan and to prevent diseases. This does not, however, mean that reactive species (RS) and redox signalling are unimportant. Ultimately, the most effective antioxidants may not turn out to be the best geroprotective drugs, but effective geroprotective interventions might well turn out to also have excellent, if probably indirect, antioxidant efficacy.

scholarly journals Melatonin administration prevents cardiac and diaphragmatic mitochondrial oxidative damage in senescence-accelerated mice

2007 ◽  
Vol 194 (3) ◽  
pp. 637-643 ◽  
Author(s):  
M I Rodriguez ◽  
G Escames ◽  
L C López ◽  
J A García ◽  
F Ortiz ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Chronic Treatment ◽  
Melatonin Treatment ◽  
Mitochondrial Oxidative Stress ◽  
Melatonin Administration ◽  
Age Dependent ◽  
Mitochondrial Oxidative Damage ◽  
Senescence Accelerated Mice ◽  
Ratio Reduction

Cardiac and diaphragmatic mitochondria from male SAMP8 (senescent) and SAMR1 (resistant) mice of 5 or 10 months of age were studied. Levels of lipid peroxidation (LPO), glutathione (GSH), GSH disulfide (GSSG), and GSH peroxidase and GSH reductase (GRd) activities were measured. In addition, the effect of chronic treatment with the antioxidant melatonin from 1 to 10 months of age was evaluated. Cardiac and diaphragmatic mitochondria show an age-dependent increase in LPO levels and a reduction in GSH:GSSG ratios. Chronic treatment with melatonin counteracted the age-dependent LPO increase and GSH:GSSG ratio reduction in these mitochondria. Melatonin also increased GRd activity, an effect that may account for the maintenance of the mitochondrial GSH pool. Total mitochondrial content of GSH increased after melatonin treatment. In general, the effects of age and melatonin treatment were similar in senescence-resistant mice (SAMR1) and SAMP8 cardiac and diaphragmatic mitochondria, suggesting that these mice strains display similar mitochondrial oxidative damage at the age of 10 months. The results also support the efficacy of long-term melatonin treatment in preventing the age-dependent mitochondrial oxidative stress.

scholarly journals LEVERAGING DRUG-DRUG INTERACTIONS FOR PHARMACOLOGICAL EXTENSION OF HEALTHY LIFESPAN

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S616-S616
Author(s):  
Jan Gruber
Keyword(s):  
Drug Interactions ◽  
Regulatory Network ◽  
Pharmacological Interventions ◽  
Distinct Entity ◽  
Promising Alternative ◽  
C Elegans ◽  
Ageing Processes ◽  
Age Dependent ◽  
Gene Regulatory ◽  
Traditional Approaches

Abstract Traditional approaches aimed at delaying or preventing age-dependent diseases view each disease as a distinct entity, resulting from separate pathophysiological chains of events. However, it is becoming increasing clear that even in adult animals there remains significant plasticity in terms of ageing trajectories and lifespan, suggesting that targeting ageing processes directly may be a promising alternative strategy. However, to date effects of even the most efficacious pharmacological interventions are smaller than those of ageing mutations, even when targeting the same ageing pathways. Interestingly, it has been shown that simultaneously targeting multiple ageing pathways can result in lifespan benefits that are synergistic (more than additive). We have recently shown that dramatic lifespan and healthspan extension can also be archived by leveraging interactions between drugs targeting distinct subsets of the gene-regulatory network controlling ageing of C. elegans. These interventions were highly efficacious, even when animals were treated only as adults.

scholarly journals Age-Dependent Prevalence and Frequency of Circulating t(14;18)-Positive Cells in the Peripheral Blood of Healthy Individuals

2008 ◽  
Vol 2008 (39) ◽  
pp. 44-47 ◽  
Author(s):  
G. Dolken ◽  
L. Dolken ◽  
C. Hirt ◽  
C. Fusch ◽  
C. S. Rabkin ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Healthy Individuals ◽  
Age Dependent

scholarly journals Brain age-dependent effects of acute endotoxemia on oxidative damage and mitochondrial function

2012 ◽  
Vol 1817 ◽  
pp. S97
Author(s):  
M.C. Cimolai ◽  
V. Vanasco ◽  
P. Evelson ◽  
H. Bugger ◽  
S. Alvarez
Keyword(s):  
Oxidative Damage ◽  
Mitochondrial Function ◽  
Age Dependent ◽  
Brain Age

scholarly journals Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan

2019 ◽  
Author(s):  
Lei Zhang ◽  
Xiao Dong ◽  
Moonsook Lee ◽  
Alexander Y. Maslov ◽  
Tao Wang ◽  
...  
Keyword(s):  
B Cell ◽  
Whole Genome Sequencing ◽  
Single Cell ◽  
B Lymphocytes ◽  
Genome Sequencing ◽  
Somatic Mutations ◽  
Somatic Hypermutation ◽  
Whole Genome ◽  
Healthy Individuals ◽  
Human Lifespan

Introductory paragraphThe accumulation of mutations in somatic cells have been implicated as a cause of ageing since the 1950s1,2. Yet, attempts to establish a causal relationship between somatic mutations and ageing have been constrained by the lack of methods to directly identify mutational events in primary human tissues. Here we provide detailed, genome-wide mutation frequencies and spectra of human B lymphocytes from healthy individuals across the entire human lifespan, from newborns to centenarians, using a recently developed, highly accurate single-cell whole-genome sequencing method3. We found that the number of somatic mutations increases from <500 per cell in newborns to >3,000 per cell in centenarians. We discovered mutational hotspot regions, some of which, as expected, located at immunoglobulin genes associated with somatic hypermutation. B cell-specific mutation signatures were observed associated with development, ageing or somatic hypermutation (SHM). The SHM signature strongly correlated with the signature found in human chronic lymphocytic leukemia and malignant B-cell lymphomas4, indicating that even in B cells of healthy individuals the potential cancer-causing events are already present. We also identified multiple mutations in sequence features relevant to cellular function, i.e., transcribed genes and gene regulatory regions. Such mutations increased significantly during ageing, but only at approximately half the rate of the genome average, indicating selection against mutations that impact B cell function. This first full characterization of the landscape of somatic mutations in human B lymphocytes indicates that spontaneous somatic mutations accumulating with age can be deleterious and may contribute to both the increased risk for leukemia and the functional decline of B lymphocytes in the elderly.

scholarly journals A Method for Deriving Quasi-healthy Cohorts From Clinical Data

2018 ◽  
Vol 10 ◽  
pp. 117822261877775
Author(s):  
Satoshi Irino ◽  
Yukio Kurihara
Keyword(s):  
Laboratory Test ◽  
Clinical Data ◽  
Laboratory Tests ◽  
Normal Values ◽  
Specific Reference ◽  
Reference Ranges ◽  
Healthy Individuals ◽  
Clinical Database ◽  
Age Dependent ◽  
Effective Condition

We evaluated quasi-healthy cohorts (model cohorts), derived from clinical data, to determine how well they simulated control cohorts. Control cohorts comprised individuals extracted from a public checkup database in Japan, under the condition that their values for 3 basic laboratory tests fall within specific reference ranges (3Ts condition). Model cohorts comprised outpatients, extracted from a clinical database at a hospital, under the 3Ts condition or under the condition that their values for 4 laboratory tests fall within specific reference ranges (4Ts condition). Because even a patient with a serious illness, such as cancer, may present with normal values on basic laboratory tests, one additional condition was added: the duration (1 or 3 months; 1M or 3M) during which patients were not hospitalized after their first laboratory test. For evaluations, cohorts were specified by age and sex. The 4Ts + 3M condition was the most effective condition, under which model cohorts were used to successfully simulate age-dependent changes and sex differences in laboratory test values for control cohorts. Therefore, by properly setting the conditions for extracting quasi-healthy individuals, we can derive cohorts from clinical data to simulate various types of cohorts. Although some issues with the proposed method remain to be solved, this approach presents new possibilities for using clinical data for cohort studies.

scholarly journals Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan

2019 ◽  
Vol 116 (18) ◽  
pp. 9014-9019 ◽  
Author(s):  
Lei Zhang ◽  
Xiao Dong ◽  
Moonsook Lee ◽  
Alexander Y. Maslov ◽  
Tao Wang ◽  
...  
Keyword(s):  
B Cell ◽  
Whole Genome Sequencing ◽  
Single Cell ◽  
B Lymphocytes ◽  
Genome Sequencing ◽  
Somatic Mutations ◽  
Whole Genome ◽  
Healthy Individuals ◽  
Human Lifespan ◽  
Increased Risk

Accumulation of mutations in somatic cells has been implicated as a cause of aging since the 1950s. However, attempts to establish a causal relationship between somatic mutations and aging have been constrained by the lack of methods to directly identify mutational events in primary human tissues. Here we provide genome-wide mutation frequencies and spectra of human B lymphocytes from healthy individuals across the entire human lifespan using a highly accurate single-cell whole-genome sequencing method. We found that the number of somatic mutations increases from <500 per cell in newborns to >3,000 per cell in centenarians. We discovered mutational hotspot regions, some of which, as expected, were located at Ig genes associated with somatic hypermutation (SHM). B cell–specific mutation signatures associated with development, aging, or SHM were found. The SHM signature strongly correlated with the signature found in human B cell tumors, indicating that potential cancer-causing events are already present even in B cells of healthy individuals. We also identified multiple mutations in sequence features relevant to cellular function (i.e., transcribed genes and gene regulatory regions). Such mutations increased significantly during aging, but only at approximately one-half the rate of the genome average, indicating selection against mutations that impact B cell function. This full characterization of the landscape of somatic mutations in human B lymphocytes indicates that spontaneous somatic mutations accumulating with age can be deleterious and may contribute to both the increased risk for leukemia and the functional decline of B lymphocytes in the elderly.

scholarly journals Cereals, calories and change: exploring approaches to quantification in Indus archaeobotany

2017 ◽  
Vol 10 (7) ◽  
pp. 1703-1716 ◽  
Author(s):  
J. Bates ◽  
C.A. Petrie ◽  
R.N. Singh
Keyword(s):  
Late Holocene ◽  
Caloric Intake ◽  
Relative Importance ◽  
Daily Lives ◽  
Daily Caloric Intake ◽  
The People ◽  
Alternative Approach ◽  
Perceived Importance ◽  
Indus Civilisation

Abstract Several major cereal groups have been identified as staples used by the pre-urban, urban and post-urban phase populations of the Indus Civilisation (3200–1500 BCE): wheat, barley, a range of small hulled millets and also rice, though their proportional exploitation is variable across space and over time. Traditional quantification methods examine the frequency, intensity and proportionality of the use of these crops and help ascertain the ‘relative importance’ of these cereals for Indus populations. However, this notion of ‘importance’ is abstracted from the daily lives of the people using these crops and may be biased by the differential production (as well as archaeological survival) of individual cereals. This paper outlines an alternative approach to quantifying Indus cereals by investigating proportions of calories. Cereals are predominantly composed of carbohydrates and therefore provided much of the daily caloric intake among many late Holocene farming populations. The four major cereal groups cultivated by Indus farmers, however, vary greatly in terms of calories per grain, and this has an impact on their proportional input to past diets. This paper demonstrates that, when converted to proportions of calories, the perceived ‘importance’ of cereals from five Indus sites changes dramatically, reducing the role of the previously dominant small hulled millet species and elevating the role of Triticoid grains. Although other factors will also have affected how a farmer perceived the role and importance of a crop, including its ecological tolerances, investments required to grow it, and the crop’s role in the economy, this papers suggests that some consideration of what cereals meant in terms of daily lives is needed alongside the more abstracted quantification methods that have traditionally been applied.

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