Genetic factors in aging
The last two decades have been a revolution for human genetics, starting with the sequencing of a human genome in 2003 and breakthroughs in genome-wide association studies finding thousands of genetic loci associated with complex human traits, including many age-related diseases.It should also be noted that sex differences in dementia incidence may be partially explained by selective survival (Shaw et al., 2021).A recent analysis in UK Biobank found that abundant mtDNA, estimated from the weighted intensities of probes mapped to the mitochondrial genome, was significantly elevated in premenopausal women compared to men and inversely associated with age, smoking, BMI, and frailty (Hagg et al., 2020).Experiments in worms, flies, and mice have shown that overexpressing chaperones and heat-shock proteins are associated with an extended lifespan, whereas models deficient in parts of the chaperone-heat-shock system present accelerated aging phenotypes (Lopez-Otin et al., 2013; Ferrucci et al., 2020).The first views frailty as a physical syndrome with a discrete categorization of individuals into nonfrail, prefrail, and frail, whereas the latter considers frailty as a multidimensional construct based on the accumulation of deficits in physical, biological, and psychosocial domains.The key pathways include the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway, mechanistic target of rapamycin (mTOR), and adenosine monophosphate-activated protein kinase (AMPK) pathway (Pignatti et al., 2020).Over the past years, there has been intensive research on how nutrient-sensing pathways control lifespan and healthspan, with the most significant breakthroughs achieved in unraveling how different dietary restrictions improve aging outcomes and survival in several species, including humans (Templeman and Murphy, 2018).For aging, gene discoveries have been sparse, although lately, large cohorts such as the UK Biobank have enabled powerful analyses of parental lifespan, healthspan, and longevity (Timmers et al., 2019; Zenin et al., 2019; Melzer et al., 2020).Recent findings in this area point toward sexual dimorphism in transcriptomic profiles with hormone-related regulation and associations with various processes such as tissue morphogenesis, fat metabolism, cancer, and immune responses (Oliva et al., 2020).For example, such sex-specific targeting patterns of transcription factors have been found for genes associated to Alzheimer's disease (AD), Parkinson's disease (PD), diabetes, autoimmune thyroid disease, and cardiomyopathy (Lopes-Ramos et al., 2020).Mitochondria-linked mechanisms
Mitochondrial DNA (mtDNA) is inherited from mothers and contains the genetic code for 13 proteins, essential components of oxidative phosphorylation complexes, and several RNAs (Kauppila et al., 2017).The most well-studied mechanisms are acetylation and methylation processes; changes in histone acetylation/methylation have been linked to aging, healthspan, and lifespan in diverse models, such as flies, mice, yeast, and human cell lines (Yi and Kim, 2020).The former refers to changes in the adaptive immune system, such as increased numbers of memory CD8 +T cells (resulting in a decreased CD4/CD8 cell ratio), loss of the key costimulatory molecule CD28 on the T cell surface and compromised clonal expansion and specific antibody production in the B cell compartment (Gubbels Bupp, 2015; Franceschi, 2019).Between puberty and menopause - when differences in the hormonal milieu are the greatest between men and women - women experience lower rates of infections, an advantage attributed to stronger immune and vaccine responses and more efficient pathogen clearance (Gubbels Bupp, 2015).These pathways regulate a multitude of intracellular functions, such as cell cycle control, DNA replication and repair, autophagy, and antioxidant defenses, by which their effects are excreted for reproduction, growth, and aging (Pignatti et al., 2020).Events such as critically short telomeres, oxidative stress, replicative errors, mitochondrial dysfunction, pathogen response, oncogene activation, and other stress sources may induce senescence of the cell with irreversible replicative arrest (Lopez-Otin et al., 2013).During aging, the balance in the protein machinery is lost and unfolded and misfolded proteins can aggregate and cause pathological conditions seen in diseases of (neuro)degeneration, AD, PD, and diabetes (Hipp et al., 2019).Analyses on sexual dimorphism in human protein homeostasis and autophagy aging processes are still lacking, which is understandable, as efficient high-throughput methods are not yet available (Ferrucci et al., 2020; Pomatto et al., 2017).Studies investigating genome-wide DNA methylation differences between men and women report significant differences in autosomes and on the X chromosome, the latter being linked to sexual dimorphism genes and XCI (Li et al., 2020c; McCartney et al., 2019).Inflammaging refers to chronic, low-grade inflammation that occurs in the absence of infection and manifests as increased production of proinflammatory cytokines, linked to both frailty and CVD (Ferrucci and Fabbri, 2018).Sex differences are present in diverse species ranging from insects to mammals, with female individuals presenting stronger innate and adaptive immune responses than males (Klein and Flanagan, 2016).Each of the hallmarks of aging is associated with undesirable metabolic alterations (Lopez-Otin et al., 2016), stressing the fact that nutrient sensing and metabolism are interlinked processes with broad effects on whole-organism functions.Interestingly, genetic polymorphisms in genes encoding proteins in the insulin/IGF and mTOR pathways are among those that are robustly associated with longevity, such that variants associated with the lower basal activity of the pathways are associated with longevity (Pan and Finkel, 2017).One of the most commonly used and strongest markers for human population-based estimation of death risk is a simple assessment of walking speed (Ganna and Ingelsson, 2015), yet other popular measures include grip strength, chair rise, lung function, vision, and an abundance of cognitive domains (Peiffer et al., 2010).Sex-specific differences are seen across almost all respiratory structures and functions; women have smaller and anatomically different lungs than men, perform worse in breathing exercises, and sex hormones interact with lung and airway function during early developmental processes and aging (LoMauro and Aliverti, 2018).Perhaps, the sex specificity in functional measures best describes the complex interplay between fitness and aging in line with the rate of living theory in the senescence theory of aging, emphasizing the sex paradox in aging where women with worse physical function and health still outlive men, possibly due to a better cellular maintenance system and protections from estrogens.However, CVD is also tightly linked to inflammaging of the vasculature, and cellular senescence that could be reflected as TL shortening and intrinsic epigenetic age acceleration (Ferrucci and Fabbri, 2018).Few efforts have been made for X chromosome-wide association studies, but they reveal (sex-specific) links to several complex traits and identify a locus associated with height escaping XCI (Bernabeu, 2020; Tukiainen et al., 2014).The X chromosome encodes approximately a thousand genes, many related to metabolic activity, such as amino acid turnover and transport, and could explain the differential proliferative rates in sexes seen during embryonic growth (Patrat et al., 2020).This state causes a response of cytokines and other proinflammatory factors to be released, which may trigger downstream effects in the surrounding tissue and invoke a senescence-associated secretory phenotype (SASP) (Ferrucci et al., 2020).Hence, cellular senescence is a core mechanism in the senescence theory of aging, where cells and tissues accumulate damage across life but is also essential in the Hayflick limit's programmed theory of aging (Ferrucci et al., 2020; Khosla et al., 2020; Schafer et al., 2020).Genetic studies of epigenetic clocks have discovered several loci associated with lifespan and lifestyle factors beyond the gene regions where the CpGs themselves are located (Lu et al., 2018; McCartney, 2020).Moreover, intrinsic and extrinsic epigenetic clocks have been suggested to represent internal (cellular) versus external (lifestyle stressor) aging processes (Horvath and Raj, 2018).From an evolutionary perspective, inflammaging can result from positive selection of genetic variants that associate with higher levels of pro-inflammatory factors and enhanced immune responses in early life, conferring better protection against pathogens but resulting in increased damage to host tissues in later life.Inflammaging is thus in accordance with multiple different theories, where various stimuli, such as oxidative stress and lifestyle factors, contribute as well (Franceschi, 2019; De la Fuente and Miquel, 2009).As stated above, men seem to experience immunosenescence to a greater extent than women, potentially because women exhibit higher basal immunoglobulin levels, higher CD4 +T cell counts, and an increased CD4/CD8 T cell ratio compared to men (Gubbels Bupp, 2015; Gomez et al., 2018).The corresponding adaptive immune functions, such as antigen-specific antibody responses and CD4 +T cell cytokine production, are also typically more enhanced in women (Gubbels Bupp, 2015; Gomez et al., 2018).Of the different dietary restrictions, the most compelling evidence rests on caloric restriction (CR), in which the energy intake is reduced ~30% relative to ad libitum-fed animals without reducing the intake of micronutrients (Templeman and Murphy, 2018).Sex hormones regulate several key functions in nutrient sensing and metabolism of glucose, amino acids, and proteins, and it is not surprising that men and women differ in several metabolic characteristics.Akin to epigenetic clocks (see Epigenetic alterations) that predict mortality independent of other risk factors, there have been attempts to create similar composite measures based on metabolites measured using different techniques (Jylhava et al., 2017).Hence, little is known about sex-specific genetic effects for complex traits, although sexual dimorphisms have been reported for anthropometric traits and gout (Bernabeu, 2020; Randall et al., 2013), and gene-sex interactions have been found for multiple sclerosis (Traglia et al., 2017).During aging, the XCI ratio between maternal and paternal X chromosomes is no longer equal, leading to skewed XCI, which has been implicated in diseases and shown to be less severe in female centenarians (Gentilini et al., 2012).Studies in rodents and in Drosophila support the association between DNA repair, mutational burden, and aging; however, sex-specific effects are intricate, and the results depend heavily on animal strain and environmental conditions (Fischer and Riddle, 2018).Taken together, the examples described here relate to chromosomal stability and resemble well with the senescence theory of aging, where random events occur over time with less capacity of our maintenance system to repair and fix the faults.Sexual dimorphism in genome-wide studies for anthropometric traits may be consistent with the developmental processes and growth controlled during early life and aging, where hormonal influences are also apparent.Oxidative damage and increased ROS production across life were initially thought to cause this dysfunction, but research in recent years showed that ROS do not accelerate aging in mice and even prolong lifespan in yeast and C. elegans (Lopez-Otin et al., 2013).In the elderly, cellular senescence is apparent where DNA maintenance and repair are no longer efficient, and telomeres reach critical lengths for cellular survival consistent with a person's natural lifespan limit (Steenstrup et al., 2017).Recently, a model using hyperlong telomeres showed that this phenotype increases the lifespan in mice and shows overall beneficial effects on metabolism, glucose control, and mitochondrial function (Munoz-Lorente et al., 2019).A mutation in the DKC1 gene on the X chromosome - a gene involved in telomere biology - is often seen in patients with dyskeratosis congenita, which leads to rapid TL shortening and reduced survival (Savage and Bertuch, 2010).However, a recent meta-analysis investigated sex differences in TL across 51 vertebrate species and found no evidence supporting either the heterogametic sex disadvantage or the sexual selection hypotheses (Remot et al., 2020).Cellular senescence is tightly linked with aging, has been well correlated with DNA damage, and an increasing number of cells are senescent in old tissues compared to young tissues in a study of liver tissue in mice (Lopez-Otin et al., 2013; Khosla et al., 2020).Nevertheless, the systemic accumulation of senescent cells in aging has been associated with many age-related diseases and conditions, such as frailty, both in humans and animal models (Ferrucci et al., 2020; Khosla et al., 2020; Schafer et al., 2020).A study by Klein et al., 2019 found that tau may affect histone acetylation in the human brain using an epigenome-wide association study of H3K9ac, thus relating histone modification processes to AD pathology.While both sexes experience aging-associated changes in the immune system, the hallmark features differ for men and women, and men are considered to experience maladaptive changes to a greater extent (Gubbels Bupp, 2015; Gomez et al., 2018).The FAI includes muscle strength (grip strength), movement (gait speed), sensory (vision and hearing), and lung function and is predictive of mortality in both sexes, yet the hazard ratio is greater in women (Finkel et al., 2019).Although frailty often coexists with multimorbidity (and disability), the association between frailty and mortality is independent of multimorbidity (Hanlon et al., 2018), indicating that frailty captures health-related variation that is not attributed to diseases alone.There is currently no widely accepted consensus on how to measure frailty; however, the two most commonly used approaches are the Fried phenotypic model (FP) (Fried et al., 2001) and the Rockwood frailty index (FI) (Searle et al., 2008).However, another theory suggested underlying the sex differences is the chronic disease hypothesis by which women are more likely to experience nonlethal chronic conditions, while men tend to develop acute conditions associated with high mortality, such as stroke and myocardial infarction (Gladyshev, 2014; Bernabeu, 2020).Hence, genomic instability, including the accumulation of mutations, epigenetic alterations, and telomere attrition, are hallmarks of aging and provide a link between aging and sexual dimorphism mechanisms in cancer.Cognitive aging in healthy adults demonstrates sex-differential effects, where men generally perform better in visuospatial ability and women better in verbal ability, but the speed of decline may be worse in men, although the literature is not consistent (Li et al., 2020b; McCarrey et al., 2016).Hence, many genes may be linked to the underlying aging process or beneficial for age-related diseases, with importance for longevity, health, and lifespan, but they may not have been specifically selected for (Rattan, 2000).Rare somatic mutations may accumulate across life and play a role in cancer, where men have been shown to have mutation accumulation earlier in life (Podolskiy et al., 2016), and in several premature-aging syndromes (Fischer and Riddle, 2018).In humans, studies have linked the accumulated burden of mutations in mtDNA to aging and PD, although a majority of the mtDNA molecules within a cell must be affected for critical symptoms to emerge (Kauppila et al., 2017).In humans, women show higher mitochondrial gene expression levels, protein content, and overall activity in multiple tissues, such as the brain, skeletal muscle, and cardiomyocytes (Ventura-Clapier et al., 2017).There are four major types of epigenetic mechanisms: ATP-dependent chromatin remodeling complexes, histone, and DNA modifications, and noncoding RNAs (Pagiatakis et al., 2021).Moreover, in women, earlier menopause, either natural or surgical, is associated with increased epigenetic age, and although the finding was not consistent across different tissues, there was further support for lower epigenetic age in women undergoing HRT (Levine et al., 2016).However, after the age of menopause, the incidence of autoimmune diseases in women decreases close to the numbers observed in men, whereas the incidence of chronic inflammatory diseases increases (Gubbels Bupp, 2015).A recent study using sequencing and flow cytometry data in blood mononuclear cells further elucidated the sexual dimorphism in immune aging by showing that male and female cells also significantly differ at the age when sex hormones decline (Marquez et al., 2020).Frailty
Frailty is defined as a state of increased vulnerability to stressors resulting from decreased physiological reserves to maintain homeostasis across multiple organ systems.(For a more in-depth discussion on sex and gender aspects in aging diseases and treatment, we refer the reader to Mauvais-Jarvis et al., 2020 and Regitz-Zagrosek, 2012).Longevity is known to be moderately heritable (Melzer et al., 2020); however, from an evolutionary perspective, natural selection is active for the reproduction of a species and not for maximizing lifespan.Another recent study found measured and genetically predicted levels of ten serum biomarkers to be associated with healthspan and lifespan, and again with stronger effects for healthspan seen in women (Li et al., 2021).However, evidence from both human and animal studies points toward the fact that the accumulation of mtDNA mutations is a feature of early life replication errors that undergo polyclonal expansion independent of ROS (Lopez-Otin et al., 2013).Substantial sexual dimorphism has been observed for mitochondrial function concerning oxidative capacity and enzyme activity (Ventura-Clapier et al., 2017).Therefore, throughout life, the length of the telomere (TL) decreases and serves as a marker of cellular aging (Blackburn et al., 2015).As such, short TL has been associated with age-related outcomes and health aspects, for example mortality (Wang et al., 2018), CVD (Haycock et al., 2014), and different stressors in life (Starkweather et al., 2014).Different genetic models have been used in mice to lengthen telomeres with telomerase activation, where some experiments increased the cancer incidence, while others did not (Folgueras et al., 2018).These findings have led to increased knowledge, and many studies have provided evidence for causal associations between short leukocyte TLs and age-related diseases (Kuo et al., 2019).Genetic liability contributes to the overall length of telomeres in all cells, and across the lifespan, stressors and lifestyle factors influence cell-specific attrition rates.Evidence points to the fact that female stem cells have an increased capacity for regeneration, self-renewal, and proliferation (Dulken and Brunet, 2015), in line with a more beneficial cellular aging route in females/women.Proteostasis and autophagy
Protein homeostasis, or proteostasis, is the body's ability to maintain control over protein synthesis, folding, stability, degradation, and removal through autophagy (Hipp et al., 2019).A study by Ubaida-Mohien et al. found a decreased representation of chaperone proteins in old skeletal muscle tissue in healthy adults, although autophagy-related proteins were overrepresented (Ubaida-Mohien et al., 2019).In model systems, abrogation of autophagy leads to neurodegeneration and shortens lifespan, whereas increased basal activity of autophagy increases lifespan (Leidal et al., 2018).Hence, declining proteostasis control in aging may be an effect of accumulated aggregates and dysfunctional autophagy, consistent with the senescent wear-and-tear theory of aging, including the ROS theory of aging.However, in human studies, genome-wide DNA methylation arrays have paved the way for a new field of research on epigenetic age where hundreds of (un)methylated sites (CpGs) have been shown to associate with age across the life course (Zhang et al., 2020).A multitude of clocks quantifying biological age across tissues, in whole blood, skin, muscle, or in human cell culture models have emerged (Horvath and Raj, 2018) and recently across mammalian species (Lu, 2021).With remarkable accuracy, clock ticks with aging and a higher epigenetic age are associated with worse health and increased mortality risk (Horvath and Raj, 2018; Chen et al., 2016).Little is known about sex-dimorphic effects on histone modifications in aging, although studies on different interventions and acetylation/methylation in animals suggest that these effects are important modifiers in aging (Fischer and Riddle, 2018).The temporal dynamics of these changes point to the crucial role of sex hormones in shaping immune aging, although it is likely much more complicated, involving an interplay of multiple homeostatic systems.Like humans, the differences are largely attributable to the effects of sex hormones, with a contribution of genetic differences due to several immunoinflammatory genes that are X chromosome encoded (Klein and Flanagan, 2016).At the molecular level, women have lower fasting insulin and glucose levels, lower basal fat oxidation, and higher fat use but lower consumption of carbohydrates during physical activity (Comitato et al., 2015).Cardiac remodeling due to aging is universal, but the decline in myocytes and systolic function are greater in males, both in humans and rodents (Keller and Howlett, 2016).However, evidence supporting this conception is not conclusive (Merrill et al., 1997; Macintyre et al., 1999), and the underlying mechanisms for the sex-frailty paradox remain unresolved.Few studies have reported that aged female mice exhibit higher FI scores than males (Heinze-Milne et al., 2019).However, there is some evidence that while most transcription factors have similar expression profiles in men and women, there may be sex-specific regulatory networks across different tissues, leading to altered function and disease control (Lopes-Ramos et al., 2020).Telomeres
Telomeres are repeated sequences of nucleotide bases (TTAGGG)n located at the end of the chromosomes (Blackburn et al., 2015).Although most telomere-related genes have been found in autosomal chromosomes, it has been suggested that the unguarded chromosome in heterogametic sex is a disadvantage for mortality and telomere maintenance.Currently, there is also increasing evidence for the beneficial antiaging effect of senolytic drugs as potential treatments to remove senescent cells when abundant (Ferrucci et al., 2020).In humans, long-lived families have a better-maintained autophagy system, and individuals under starvation exhibit enhanced autophagic flux (Leidal et al., 2018).Females studied in animals and model systems also exhibit more resistance to stressors, partly hypothesized to be due to estrogens' beneficial effects (Tower et al., 2020).As with telomeres, the epigenetic clocks seem to be tightly linked with cellular replication underlying the Hayflick limit theory (Wagner, 2019).Taken together, the sexual dimorphism seen in epigenetic studies on aging is complex and seems to reflect sex chromosome-linked mechanisms and/or hormonal biological processes.Although animal models cannot fully recapitulate human immunosenescence or inflammaging, findings on sex-related immune functions in animal studies have generally been in line with observations in humans.Nutrient sensing
Intracellular nutrient-sensing pathways and signaling systems mediate information on nutrient availability and energy levels in the extracellular milieu.At the molecular level, CR triggers activation of stress response pathways that in turn reduce inflammation and increase repair and antioxidative functions.However, the higher basal insulin levels in men promote glycogen and lipid synthesis in muscle cells, resulting in higher muscle mass and strength (Comitato et al., 2015).Analogous to the Hayflick limit, the rate of aging theory posits that the total amount of energy expenditure per lifetime is finite and that excessive usage results in accelerated aging (Pearl, 2011).A recent study created a composite measure, termed the functional aging index (FAI), to better capture the state and changes in various physical functions simultaneously.As men have higher muscle mass than women, some clues might be obtained from the observed associations between higher skeletal muscle mass and higher basal metabolic rate, that is energy expenditure that is higher in men than in women (Ruggiero et al., 2008).In recent years, animal models of frailty, building on both FI and FP, have become available, providing opportunities to untangle how and why frailty develops and the mechanisms behind the sex differences.However, other studies have reported no difference between the sexes, and one study found that male mice had higher FI scores than females (Heinze-Milne et al., 2019).The top 10 leading causes of death by sex in those above 70 years reveals a change in the ranking of diseases so that instead of colon and rectum cancers, prostate cancer emerges in men and communicable diarrheal diseases in women.Similar sexual dimorphism is observed in rodent models investigating mitochondrial respiratory function (Ventura-Clapier et al., 2017).Figure 2