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Journal of the American College of... Mar 2020The genetics of human longevity has long been studied, and in this regard, centenarians represent a very informative model. Centenarians are characterized by 2 main... (Review)
Review
The genetics of human longevity has long been studied, and in this regard, centenarians represent a very informative model. Centenarians are characterized by 2 main features: 1) the capability to avoid or postpone the major age-related diseases; and 2) a high level of heterogeneity of their phenotype. The first suggests that longevity and resistance to diseases are mediated by shared mechanisms, the latter that many strategies can be used to become long lived, likely as a result of variable genome-environment interactions. The authors suggest that the complexity of genome-environment interactions must be considered within an evolutionary and ecological perspective and that the concept of "risk allele" is highly context dependent, changing with age, time, and geography. Genes involved in both longevity and cardiovascular diseases, taken as a paradigmatic example of age-related diseases, as well as other emerging topics in genetics of longevity, such as micro-ribonucleic acid (miRNA) genetics, polygenic risk scores, environmental pollutants, and somatic mutations are discussed.
Topics: Aged, 80 and over; Cardiovascular Diseases; Gene-Environment Interaction; Humans; Longevity
PubMed: 32130932
DOI: 10.1016/j.jacc.2019.12.032 -
GeroScience Aug 2023There are two fundamental questions in developmental biology. How does a single fertilized cell give rise to a whole body? and how does this body later produce progeny?... (Review)
Review
There are two fundamental questions in developmental biology. How does a single fertilized cell give rise to a whole body? and how does this body later produce progeny? Synchronization of these embryonic and postembryonic developments ensures continuity of life from one generation to the next. An enormous amount of work has been done to unravel the molecular mechanisms behind these processes, but more recently, modern developmental biology has been expanded to study development in wider contexts, including regeneration, environment, disease, and even aging. However, we have just started to understand how the mechanisms that govern development also regulate aging. This review discusses examples of signaling pathways involved in development to elucidate how their regulation influences healthspan and lifespan. Therefore, a better knowledge of developmental signaling pathways stresses the possibility of using them as innovative biomarkers and targets for aging and age-related diseases.
Topics: Longevity; Signal Transduction
PubMed: 37160658
DOI: 10.1007/s11357-023-00809-2 -
Free Radical Biology & Medicine Nov 2023One of the challenges facing science/biology today is uncovering the molecular bases that support and determine animal and human longevity. Nature, in offering a... (Review)
Review
One of the challenges facing science/biology today is uncovering the molecular bases that support and determine animal and human longevity. Nature, in offering a diversity of animal species that differ in longevity by more than 5 orders of magnitude, is the best 'experimental laboratory' to achieve this aim. Mammals, in particular, can differ by more than 200-fold in longevity. For this reason, most of the available evidence on this topic derives from comparative physiology studies. But why can human beings, for instance, reach 120 years whereas rats only last at best 4 years? How does nature change the longevity of species? Longevity is a species-specific feature resulting from an evolutionary process. Long-lived animal species, including humans, show adaptations at all levels of biological organization, from metabolites to genome, supported by signaling and regulatory networks. The structural and functional features that define a long-lived species may suggest that longevity is a programmed biological property.
Topics: Rats; Humans; Animals; Longevity; Mammals; Biological Evolution; Signal Transduction; Species Specificity
PubMed: 37748717
DOI: 10.1016/j.freeradbiomed.2023.09.023 -
Biochimica Et Biophysica Acta May 2014Diseases including cancer, type 2 diabetes, cardiovascular and immune dysfunction and neurodegeneration become more prevalent as we age, and combined with the increase... (Review)
Review
Diseases including cancer, type 2 diabetes, cardiovascular and immune dysfunction and neurodegeneration become more prevalent as we age, and combined with the increase in average human lifespan, place an ever increasing burden on the health care system. In this chapter we focus on finding ways of modulating sphingolipids to prevent the development of age-associated diseases or delay their onset, both of which could improve health in elderly, fragile people. Reducing the incidence of or delaying the onset of diseases of aging has blossomed in the past decade because of advances in understanding signal transduction pathways and cellular processes, especially in model organisms, that are largely conserved in most eukaryotes and that can be modulated to reduce signs of aging and increase health span. In model organisms such interventions must also increase lifespan to be considered significant, but this is not a requirement for use in humans. The most encouraging interventions in model organisms involve lowering the concentration of one or more sphingolipids so as to reduce the activity of key signaling pathways, one of the most promising being the Target of Rapamycin Complex 1 (TORC1) protein kinase pathway. Other potential ways in which modulating sphingolipids may contribute to improving the health profile of the elderly is by reducing oxidative stresses, inflammatory responses and growth factor signaling. Lastly, perhaps the most interesting way to modulate sphingolipids and promote longevity is by lowering the activity of serine palmitoyltransferase, the first enzyme in the de novo sphingolipid biosynthesis pathway. Available data in yeasts and rodents are encouraging and as we gain insights into molecular mechanisms the strategies for improving human health by modulating sphingolipids will become more apparent. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.
Topics: Animals; Humans; Longevity; Models, Biological; Signal Transduction; Sphingolipids
PubMed: 23954556
DOI: 10.1016/j.bbalip.2013.08.006 -
Ciencia & Saude Coletiva Jan 2019
Topics: Aged; Aged, 80 and over; Aging; Brazil; Humans; Longevity; Middle Aged; Quality of Life
PubMed: 30698234
DOI: 10.1590/1413-81232018241.31212018 -
Gerontology 2018A vast body of research has demonstrated that disease susceptibility and offspring health can be influenced by perinatal factors, which include both paternal and... (Review)
Review
BACKGROUND
A vast body of research has demonstrated that disease susceptibility and offspring health can be influenced by perinatal factors, which include both paternal and maternal behavior and environment. Offspring disease risk has the potential to affect the health span and life span of offspring.
KEY FINDINGS
Various maternal factors, such as environmental toxicant exposure, diet, stress, exercise, age at conception, and longevity have the potential to influence age-associated diseases such as cardiovascular disease, obesity, diabetes, and cancer risk in offspring. Paternal factors such as diet, age at conception, and longevity can potentially impact offspring health span and life span-reducing traits as well.
PRACTICAL IMPLICATIONS
Continued research could go a long way toward defining mechanisms of the developmental origins of life span and health span, and eventually establishing regimens to avoid negative developmental influences and to encourage positive interventions to potentially increase life span and improve health span in offspring.
Topics: Animals; Cardiovascular Diseases; Developmental Biology; Diabetes Mellitus, Type 2; Diet; Disease Susceptibility; Epigenesis, Genetic; Exercise; Female; Humans; Infant, Newborn; Longevity; Male; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Seasons; Telomere Shortening
PubMed: 29324453
DOI: 10.1159/000485506 -
Genes Jul 2019Human average life expectancy in developed countries has increased dramatically in the last century, a phenomenon which is potentially accompanied by a significant rise...
Human average life expectancy in developed countries has increased dramatically in the last century, a phenomenon which is potentially accompanied by a significant rise in multi-morbidity and frailty among older individuals.[...].
Topics: Genome, Human; Human Genetics; Humans; Longevity
PubMed: 31370355
DOI: 10.3390/genes10080585 -
Genome Biology Mar 2023Ageing is inherent to all human beings, yet why we age remains a hotly contested topic. Most mechanistic explanations of ageing posit that ageing is caused by the... (Review)
Review
Ageing is inherent to all human beings, yet why we age remains a hotly contested topic. Most mechanistic explanations of ageing posit that ageing is caused by the accumulation of one or more forms of molecular damage. Here, I propose that we age not because of inevitable damage to the hardware but rather because of intrinsic design flaws in the software, defined as the DNA code that orchestrates how a single cell develops into an adult organism. As the developmental software runs, its sequence of events is reflected in shifting cellular epigenetic states. Overall, I suggest that to understand ageing we need to decode our software and the flow of epigenetic information throughout the life course.
Topics: Humans; Longevity; Software Design; Aging; Selection, Genetic
PubMed: 36973715
DOI: 10.1186/s13059-023-02888-y -
The Journals of Gerontology. Series A,... Nov 2019Interventions meant to promote longevity and healthy aging have often been designed or observed to modulate very specific gene or protein targets. If there are naturally... (Review)
Review
Interventions meant to promote longevity and healthy aging have often been designed or observed to modulate very specific gene or protein targets. If there are naturally occurring genetic variants in such a target that affect longevity as well as the molecular function of that target (eg, the variants influence the expression of the target, acting as "expression quantitative trait loci" or "eQTLs"), this could support a causal relationship between the pharmacologic modulation of the target and longevity and thereby validate the target at some level. We considered the gene targets of many pharmacologic interventions hypothesized to enhance human longevity and explored how many variants there are in those targets that affect gene function (eg, as expression quantitative trait loci). We also determined whether variants in genes associated with longevity-related phenotypes affect gene function or are in linkage disequilibrium with variants that do, and whether pharmacologic studies point to compounds exhibiting activity against those genes. Our results are somewhat ambiguous, suggesting that integrating genetic association study results with functional genomic and pharmacologic studies is necessary to shed light on genetically mediated targets for longevity-enhancing drugs. Such integration will require more sophisticated data sets, phenotypic definitions, and bioinformatics approaches to be useful.
Topics: Forecasting; Humans; Longevity; Preliminary Data; Quantitative Trait Loci
PubMed: 31724058
DOI: 10.1093/gerona/glz206 -
Neuroscience and Biobehavioral Reviews Jan 2020Increased healthcare and pharmaceutical understanding has led to the eradication of many childhood, infectious and preventable diseases; however, we are now experiencing... (Review)
Review
Increased healthcare and pharmaceutical understanding has led to the eradication of many childhood, infectious and preventable diseases; however, we are now experiencing the impact of aging disorders as the lifespan increases. These disorders have already become a major burden on society and threaten to become a defining challenge of our generation. Indications such as Alzheimer's disease gain headlines and have focused the thinking of many towards dementia and cognitive decline in aging. Indications related to neurological function and related behaviors are thus an extremely important starting point in the consideration of therapeutics.However, the reality is that pathological aging covers a spectrum of significant neurological and peripheral indications. Development of therapeutics to treat aging and age-related disorders is therefore a huge need, but represents a largely unexplored path. Fundamental scientific questions need to be considered as we embark towards a goal of improving health in old age, including how we 1) define aging as a therapeutic target, 2) model aging preclinically and 3) effectively translate from preclinical models to man. Furthermore, the challenges associated with identifying novel therapeutics in a financial, regulatory and clinical sense need to be contemplated carefully to ensure we address the unmet need in our increasingly elderly population. The complexity of the challenge requires different perspectives, cross-functional partnerships and diverse concepts. We seek to raise issues to guide the field, considering the current state of thinking to aid in identifying roadblocks and important challenges early. The need for therapeutics that address aging and age-related disorders is acute, but the promise of effective treatments provides huge opportunities that, as a community, we all seek to enable effectively as soon as possible.
Topics: Aging; Animals; Chronic Disease; Drug Development; Humans; Longevity
PubMed: 31783058
DOI: 10.1016/j.neubiorev.2019.11.021