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Gerontology. Author manuscript; available in PMC 2019 January 12.
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Published in final edited form as:

Gerontology. 2018 ; 64(3): 237–245. doi:10.1159/000485506.

Developmental Origins of Health Span and Life Span: A Mini

Review
Joshua D. Preston1, Leryn J. Reynolds2, and Kevin J. Pearson1
1Pharmacology & Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY
2Department of Human Movement Sciences, Old Dominion University Darden College of
Education, Norfolk, VA
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Abstract
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.
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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.

Keywords
Aging; Developmental Origins of Health and Disease; Developmental Programming; Disease;
Epigenetics; Exercise; Longevity; Pregnancy

1.0 Introduction
The field studying the developmental origins of health and disease hypothesis has been an
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emerging and rapidly growing area of research for several decades. This hypothesis strongly
suggests that multiple factors during pre-pregnancy, gestation, and the early postnatal period
influence long-lasting disease susceptibility in offspring [1]. Markers of offspring health and
even life span can be influenced by numerous maternal and paternal factors, and it is likely
that many of these parental effects are transferred by multiple molecular mechanisms,
including epigenetic regulation [1].

Corresponding Author: Kevin J. Pearson, University of Kentucky, 900 S. Limestone, C.T. Wethington Bldg 591, Lexington, KY
40536, [email protected], 859-218-1371.
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The primary purpose of this mini-review is to highlight areas of the existing literature where
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the maternal and early postnatal environments influence later life obesity, type 2 diabetes
mellitus (T2DM), and cardiovascular disease (CVD) risk in offspring because these diseases
have been shown to substantially reduce life expectancy [2,3]. However, we will also briefly
explore additional disease outcomes and less studied areas such as paternal influences prior
to conception. While most work has focused on negative effects on offspring disease, there
is a growing body of evidence that positive interventions such as maternal exercise could be
used to improve offspring health span [4]. Regardless, preconception, pregnancy, and early
postnatal life appear to be a short-term window where healthy behaviors could provide a
lifetime of health benefits to offspring.

2.0 Parental Diet, Obesity, and Diabetes

Hales and Barker hypothesized in a 1992 paper that maternal undernutrition could retard the
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growth of fetal beta cells in utero and subsequently lead to T2DM and metabolic syndrome
in adult life; this hypothesis is known as the “thrifty phenotype hypothesis” because a fetus
can be forced to assume its most thrifty phenotype tailored to a maternally undernourished
environment [5]. Barker et al. [6] provided a subsequent review on how in utero nutrition
affected offspring CVD risk and development. These early reviews sparked intense research
into how the maternal milieu could influence offspring phenotypes, and this field later fell
under the developmental origins of health and disease hypothesis [1]. Multiple retrospective
analyses have been performed in humans, and subsequent animal studies have attempted to
delineate mechanisms. For an excellent review on work being performed in the
developmental origins of health and disease field, see Wadhwa et al. [1], and for an overview
of epigenetics and further reading on epigenetic mechanisms, see Holliday [7].
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2.1 Human Studies

2.1.1 Maternal Diabetes—A vast body of literature has reflected that diabetes during
pregnancy can have long lasting metabolic effects on offspring. One prime example of this
can be seen in studies conducted in Pima Indians. These studies indicate that maternal
diabetes poses a significant risk to offspring development of T2DM, higher systolic blood
pressure and hemoglobin A1c, and greater rates of obesity [8–10]. Drawing on a large body
of evidence, Simeoni and Barker assert in their review that exposure to high intrauterine
glucose concentration can independently influence T2DM risk in offspring, irrespective of
whether or not a mother has diabetes [11]. Thus, increased intrauterine glucose exposure
may contribute to the developmental origins of later disease [11]. For a meticulous review on
both human and animal studies being performed on maternal diabetes, mechanisms, and
possible epigenetic modes of transmission, see Ma et al. [12].
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2.1.2 Gestational Weight Gain and Maternal Obesity—Obese individuals represent a

rapidly growing demographic in the global population, and this disease has the potential to
affect offspring disease risk [13]. For additional information on maternal obesity and its
impact on offspring health and disease, see Lustig’s thorough review [13]. In regards to
maternal body mass index (BMI), Olson et al. [14] found that mothers with overweight or
obese BMIs during early pregnancy had children that were significantly more likely to be

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overweight at 3 years of age. Not only was early-pregnancy BMI correlated with offspring
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overweight at 3 years of age, but excessive weight gain (more than the Institute of
Medicine’s recommendation per BMI category) led to a higher risk of overweight offspring
at 3 years of age [14]. Excessive weight gain during pregnancy by mothers that were either
overweight or obese in early pregnancy aggravated this effect in offspring [14]. These
findings suggest that obesity prior to pregnancy serves as a contributor to offspring obesity,
especially if excessive weight gain occurs during pregnancy. The pathophysiology behind
the modulation of offspring health by gestational weight gain and maternal obesity remain
somewhat unknown; however, for an outstanding review on human and animal models
which explore mechanisms, see Poston [15].

2.1.3 Maternal Undernutrition—The Dutch famine was a period of intense caloric

deprivation in a specifically defined period of time during the winter of 1944–1945. Caloric
intake often dipped below 800 calories per day per person, and pregnant women were not
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excluded. As unfortunate as this event was, it served as an instance to examine the specific
effects of defined maternal caloric deprivation on offspring health in humans. One
significant finding from examining the offspring was famine-exposed babies during certain
periods of gestation had lower birth weight [16]. Low birth weight has been shown to be
associated with CVD and metabolic syndrome later in life [6,16,17].

Interestingly, the offspring health effects of maternal caloric deprivation during the Dutch
famine appear to be time specific as to when the restriction occurred during pregnancy [16].
For example, Painter et al. [16] found that exposure to famine during late pregnancy was
most closely associated with impaired glucose tolerance in offspring (measured by
significantly higher 120 minute glucose and insulin levels). Exposure to famine during mid
gestation correlated with increased incidence of microalbuminuria and obstructive airway
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disease in offspring [16]. Lastly, babies exposed to famine during early gestation, while not
having lower than average birth weight compared to their mid-late gestation exposed
counterparts, displayed increased coronary heart disease and obesity, elevated lipids, and
altered clotting later in life [16]. In cases where negative organ system outcomes can be seen
in offspring as a result of time-specific exposure, Painter et al. [16] hypothesized that energy
deprivation retards growth of the specific system that is affected. For example, since the
second trimester is a period of rapid nephron and bronchial development, undernutrition
during these periods could lead to negative, organ-specific health outcomes in adult
offspring such as microalbuminuria or obstructive airway disease [16].

Barker et al. [6] suggest that low birth weight in offspring of mothers who are calorically
restricted in late pregnancy could be due to placental function taking precedence over fetal
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growth, and such low birth weight may predispose offspring to CVD. However, despite low
birth weight being associated with CVD and metabolic syndrome [6,17], many of the
findings regarding health outcomes of adult offspring from Painter et al. [16] were
independent of the birth weight, which suggests that caloric deprivation may play an
independent role in the fetal origins of adult diseases. Epigenetic regulation, and particularly
DNA methylation, seems to potentially influence this process, as Heijmans et al. [18] found
that offspring exposed to the Dutch famine 6 decades prior displayed persistent DNA

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hypomethylation of the differentially methylated region of the insulin-like growth factor

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(IGF) 2 gene in comparison to same-sex, unexposed siblings.

It is important to note that while low birth weight has a correlation with later life metabolic
dysfunctions, it may not be a causal mechanism. Rather, it is likely a co-factor that is
accompanied by the modification of other mechanisms that set the trajectory for later life
metabolic function, as Barker et al. [6] assert that birth weight is simply a surrogate for
programmed phenotypes. For example, findings from the 1958 British Birth Cohort indicate
that prenatal exposures certainly have the power to influence later-life glucose metabolism;
however, this was mediated largely through adiposity in offspring rather than birth weight
[19]. It is possible that low birth weight babies experience a phenomenon known as “catch-
up growth,” which may be predisposing them to increased CVD risk and metabolic disease
later in life (mouse models which test this directly are discussed in section 2.2.3).
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Unfortunately, fetal nutritional restriction does not just increase offspring CVD and
metabolic disease rates, but can impact cancer risk and cognitive function later in life as
well. Painter et al. [20] found a significantly higher incidence of breast cancer in women
who were born to mothers exposed to Dutch famine during early pregnancy. Additionally,
adult offspring of mothers exposed to the Dutch famine during early pregnancy exhibit lower
performance on a “selective attention task” at age 56–59 [21]. This may suggest an
increased rate of age-associated deterioration and cognitive decline in offspring exposed
during early gestation [21]. Mechanisms that govern these two phenomena remain
speculative. Taken together, these findings are indicative that prenatal undernutrition does
not limit its effects to metabolic damage in offspring, but can also affect other age-associated
diseases which could impact health span and life span.
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2.1.4 Paternal and Grandpaternal Diet—Paternal diet appears to have the potential to
alter both positive and negative offspring phenotypes. Studies of Swedish birth cohorts
found that fathers who experienced low food availability during their “slow growth period”
(defined as ages 9–12 for men) had offspring that showed lower CVD mortality [22].
Moreover, subjects in one Swedish birth cohort displayed increased survival if their paternal
grandfather experienced low food availability during their slow growth period. However,
negative phenotypes can arise as well, as excess food availability had the opposite effect
[23]. Additionally, subjects displayed increased diabetes mortality when the paternal
grandfather lived through high food availability during their slow growth period [22]. The
mechanisms behind the effect of grandpaternal diet remain elusive, but both Kaati et al. and
Bygren et al. have suggested genomic imprinting as a likely explanation [22,23]. For an
excellent discussion on genomic imprinting and potential transgenerational effects, see
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Pembrey [24]. Food restriction can have a very different effect depending on the timing, as
Veenendaal et al. found that fathers who were undernourished in gestation (F1) due to the
Dutch famine had offspring (F2) that were more obese. Interestingly, this effect was not seen
in offspring of mothers undernourished in utero [25]. Taken together, these findings indicate
that paternal and grandpaternal diet may lead to both positive and negative phenotypes in
offspring, although this effect depends largely on timing and feeding behavior. For rat
models that test the effect of high fat diet on transgenerational metabolism, see Chambers et
al. [26].

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2.1.5 Model Systems to Study Developmental Origins in Humans—Our

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laboratory has recently begun using neonatal skin to study in utero exposures and possible
mechanisms that could contribute to later disease risk [27]. Primary dermal fibroblasts from
foreskin samples can be used as a living, functional system to study the potential insulin
signaling, adipogenesis, or stress response differences resulting from different in utero
exposures [27]. Further, skin biopsies could be taken in the same subject later in life for
longitudinal measures as the person ages.

2.2 Animal Studies

Animal studies provide for more specific interventions compared to human studies, which
are frequently limited to retrospective data analyses. The following is not all-inclusive but
attempts to highlight relevant animal studies in regards to perinatal influences on offspring
age-associated diseases, health span, and life span.
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2.2.1 Maternal Dietary Interventions—Samuelsson et al. [28] found that female mice
fed a high fat diet prior to mating and during pregnancy and nursing had offspring that
exhibited increased adiposity, glucose intolerance, and hypertension once weaned onto
regular diets. In addition, Alfaradhi et al. [29] found high fat diet fed female mice had
offspring that exhibited non-alcoholic fatty liver disease, oxidative damage in the liver of
these offspring, and insulin resistance at 8 weeks of age, prior to the development of
increased adiposity; thus, Alfaradhi et al. propose that oxidative damage could be a
mechanism by which the offspring develop non-alcoholic fatty liver disease and insulin
resistance. Additionally, Taheripour et al. [30] demonstrated in a swine model that offspring
of mothers who consumed high-energy diets during pregnancy displayed impaired vascular
function. This was expressed in the form of reduced vasorelaxation in offspring femoral
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arteries (measured by endothelial-dependent and -independent vasorelaxation), which may

be a risk factor for atherosclerosis. Indeed, similar mechanisms may be at play in the
impaired vascular function of 3-month-old mouse offspring of high fat diet-fed dams, as
these mice were hypertensive and exhibited endothelial dysfunction [28]. These studies
indicate that maternal high fat and/or high-energy diets can lead to negative and potentially
life span-reducing phenotypes in offspring. Conversely, positive maternal dietary
interventions have been demonstrated in mouse models in the past. For example, Harman
and Eddy’s study found that dams that were fed a diet supplemented with the antioxidant 2-
mercaptoethylamine during pregnancy had offspring who experienced significantly
increased average life spans compared to controls (14.7 and 8.6% for male and female
offspring, respectively) [31].

2.2.2 Early Body Size, Crowded-Litter, and Preweaning Protein Restriction—

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While many dietary interventions in the developmental origins of health and disease field
depend on maternal diet during pregnancy, a significant body of literature asserts that
perinatal influences such as postnatal caloric restriction and maternal low protein diets
(during lactation) can have significant effects on offspring life span. It has been shown that
mice that are calorically restricted in early life (first 20 days) via 50% litter enlargement
show an 18% increase in median life span compared to controls [32]. Ozanne and Hales

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demonstrated that male mice that were nursed by a mother that was on a low-protein diet
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during lactation outlived controls (814 vs. 765 days of average age at death) [33].

In a laboratory setting, caloric restriction enacted during adulthood has been shown to delay
the onset of age-associated diseases and improve survival in numerous species. The
emerging literature discussed above suggests that a similar effect of life span extension can
be seen from caloric restriction and protein restriction in early postnatal life, but not in utero,
even if mice are weaned onto a normal, ad libitum diet after weaning [32,33].

Male mice nursing from low-protein-fed dams challenged with an obesity-inducing diet after
weaning showed significantly increased life span compared to controls fed the same obesity-
inducing diet (807 vs. 715 days of average age at death) [33]. Also, adult rats born to dams
that were protein restricted during lactation showed lower body weight and adiposity as well
as improved glucose homeostasis compared to controls [34]. Interestingly, offspring nursed
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by low-protein fed dams or born into large litters (both early mechanisms of calorie
restriction) are seemingly not programmed to restrict their calorie intake throughout later
life, as adult postnatal low protein offspring showed no differences in food intake compared
to controls [34], and crowded-litter male mice also showed no differences in food intake
compared to control mice at 6 months of age [35]. This may suggest that the positive effects
seen in enlarged litter and postnatal low protein offspring are not due to lower food intake,
but rather early metabolic programming.

It is possible that the mechanisms that mediate perinatal metabolic programming fall under
the general phenomenon of body size-dependent life span trajectory. Indeed, postnatal low
protein rats showed persistently lower body weights from nursing to adulthood [34]. It has
been established that decreased body size (ages 2 to 24 months) can predict life span in mice
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[36], but this should not be confused with low birth weight. For further reading on animal
models of early nutritional restriction and aging, see Davis et al. [37].

2.2.3 Catch-Up Growth—Mouse models have demonstrated that male mice which are
undernourished prenatally via maternal low-protein diet and then cross-fostered to control
fed dams experience a marked decrease in average age at death compared to controls. Cross-
fostering to control fed dams results in greater nutritional intake directly after prenatal
undernutrition, and initiates what Ozanne and Hales have deemed “catch-up growth,”
(mentioned above as being potentially at play in humans with low birth weights) [33].
Furthermore, this difference was exacerbated if mice were placed on obesogenic diets, as
mice exposed to prenatal caloric restriction still had significantly shorter life spans on
average than mice that were not exposed and put on the same obesogenic diet [33]. A
version of catch-up growth may partially be at play in humans and the development of later
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life metabolic syndrome and other comorbid diseases such as CVD or obesity, as Eriksson et
al. [38] found those who were thin at birth but experienced catch-up growth had increased
CVD morbidity as adults.

Sirtuin 1 (SIRT1) is a protein implicated to be involved in some of the life span-extending

effects of calorie restriction. While numerous pathways and mechanisms are likely involved,
there are data to suggest that decreased SIRT1 protein expression may play a role in the

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decreased life span that arises from catch-up growth, as Chen et al. found that male mice that
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experienced catch-up growth displayed decreased SIRT1 protein expression in muscle tissue
compared to controls [39].

3.0 Environmental Toxicants

Prenatal exposures to multiple environmental toxicants pose significant risk to the health of
offspring in both mouse models and humans. Correlations have been made between prenatal
cigarette smoke exposure and later disease in humans [40,41] and prenatal cigarette smoke
and environmental toxicant exposure and life span-decreasing diseases in rodents [42,43].

3.0.1 Cigarette Smoke

Maternal cigarette smoke exposure remains one of the most persistent and ubiquitous
prenatal hazards. In 2014, 8.4% of US women smoked during pregnancy despite the well-
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explored negative health effects on offspring [44]. In humans, maternal smoking has been
shown to play a role in the offspring development of diseases that reduce life expectancy,
such as obesity. For example, a systematic review and meta-analysis found a positive
association of maternal smoking with childhood overweight, as well as childhood obesity
[41]. It seems that this risk also carries into adulthood, as one study found an odds ratio for
obesity of 1.56 in men and 1.41 in women at age 33 whose mothers smoked during
pregnancy; these differences remained after adjustment for confounders [40]. Additionally,
babies from the same cohort were found to have lower birth weight if their mother smoked
during pregnancy [40]. Maternal smoking’s effect on offspring metabolism has also been
tested in mouse models. Chen et al. [43] found that in dams exposed to high fat diet/chow
and sham/cigarette during pregnancy, offspring of dams exposed to smoke were more
glucose intolerant compared to controls, and this effect was exacerbated by maternal high fat
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diet.

3.0.2 Polychlorinated Biphenyls (PCBs)

PCBs are a prevalent and common environmental contaminant, contained, for example, in
insulating material, plastic softeners, and electrical equipment. Even though PCBs were
banned in the 1970s, exposure still continues today due to the lasting ability of PCBs to
contaminate groundwater and our food supply. PCBs are considered endocrine disrupting
chemicals; thus, PCBs may contribute to the development of obesity and metabolic disease
[45]. We have previously shown that perinatal PCB126 exposure can have sex-specific
effects on offspring body composition. Female offspring that were exposed perinatally to
PCBs had a dose-dependent decrease in percent lean tissue and increase in adiposity while
males had a significant reduction in lean mass in response to perinatal environmental
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contaminant exposure [42]. Current studies in our laboratory are exploring the long-term
effects of in utero and postnatal exposure to PCBs on adiposity and glucose homeostasis as
offspring age. Since obesity and impaired glucose homeostasis can decrease life expectancy,
PCBs and other environmental exposures (such as 4-nonylphenol and bisphenol A) could
potentially be a perinatal influence of life span and health span.

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4.0 Maternal Social Stress and Mental Health

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There is an emerging field of literature that explores the effects of maternal social stress and
mental health during pregnancy on offspring health and disease. Plant et al. [46] found that
prenatal depression was associated with greater rates of clinically significant inflammation
in adult offspring as measured by circulating high-sensitivity C-reactive protein independent
of adult depression or childhood maltreatment. Also, trauma and extreme stress experienced
by a mother during gestation may be a predictor of insulin resistance and higher BMI in
adult offspring, as Entringer et al. [47] showed both of these traits to be significantly
elevated in offspring born to mothers who experienced such stress. Additionally, King et al.
[48] found that some maternal social disadvantages increased methylation at the
differentially methylated regions of the maternally expressed gene 3 (MEG3) in offspring.
Because MEG3 expression has been shown to have an inverse relationship with incidence of
several cancer types, methylation of the MEG3 differentially methylated regions could
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potentially predispose offspring to cancer [48]. Together, these initial data could lead to
speculation that maternal adversity, stress, or social disadvantage could decrease offspring
life span due to cancer risk, inflammation, or metabolic disease. For an excellent review of
animal and human work being done on maternal stress and developmental origins as well as
potential mechanisms, see Brunton [49].

5.0 Parental Longevity and Age at Conception, Telomere Length, and

Season of Birth
While the prior sections have focused on factors that involve the in utero and postnatal
period, this section will outline studies that examine influences on offspring life span and
longevity such as season of birth, maternal and paternal age at conception, telomere length,
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and maternal and paternal longevity.

5.0.1 Season of Birth

Season of birth has been shown to have an influence on longevity. For example, in a study of
1880–1895 born US centenarians, it was demonstrated that the odds of becoming a
centenarian increased significantly if the month of birth was in the second half of the year
(especially September–November) as opposed to the first half of the year (specifically
March) [50]. Various prenatal and postnatal environmental factors can fluctuate as a function
of season of birth, as Gavrilov and Gavrilova propose that improved maternal nutrition,
lower rates of seasonal infection for newborns, mild ambient temperature in early life, and
potential seasonal differences in sperm quality at conception might account for the increase
in likelihood of fall babies becoming centenarians [50]. Some evidence has shown that
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sperm and semen quality can be affected by season and age [51]. Future research should
address questions of whether sperm or semen quality could influence the health and life span
of offspring. Contrarily, adverse perinatal environment could potentially act as an early
biological insult to a developing fetus or baby. These data specifically corroborate the “high
initial damage load hypothesis,” which posits that events that cause early damage in an
organism can set its life span trajectory [52]. These effects may be lessened due to

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improvements in nutrition and disease prevention in the US; nevertheless, these findings still
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provide some proof of concept for the developmental origins of life span.

5.0.2 Paternal and Maternal Longevity and Age at Conception

Moreover, paternal and maternal longevity (80+ years of age) was associated with marked
increases in the likelihood for offspring to become a centenarian [53]. Thus, this study
suggests that parental longevity can be a heritable and independent predictor of offspring
longevity. Additionally, parental age at birth/conception can be associated with offspring
longevity. Gavrilov and Gavrilova reviewed multiple studies that have found a positive effect
of younger maternal age at birth increasing the chances of offspring becoming a centenarian
[53] and also paternal age at conception being inversely proportional with longevity in
female offspring [54]. It is important to note that since the time at which parents have their
first child is increasingly delayed until later ages in the Western world [55], paternal and
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maternal age at conception could still serve as a significant factor influencing offspring life
span. Additionally, a study in mice supported the notion of younger maternal age at birth
prolonging life span in female offspring [56]. Interestingly, younger maternal age did not
have the same effect in male offspring, and older maternal age at birth even prolonged life
span of male offspring in some strains [56].

5.0.3 Telomere Length

Telomeres are structures of DNA and protein located at the end of the chromosome that help
to stabilize and protect the genome. Telomere length has been implicated to play a role in
aging, as telomere length decreases with age and shortened telomere length can affect life
span and age-related disease susceptibility. A number of studies have been performed to
examine the paternal and maternal influences on telomere length. High maternal pre-
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pregnancy BMI independently led to shorter telomere length in newborn offspring

(measured in placenta and cord blood) [57]. A study in a homogeneous Amish population
found that paternal telomere length was associated with telomere length in offspring, and
paternal life span was correlated with telomere length in female offspring [58]. These data
indicate a degree of prenatal and parental influence on offspring telomere length, and
emphasizes the importance for further research to explore such influences on telomere
length and their effect on life span and health span.

6.0 Exercise
While a majority of this review has focused attention on negative parental behaviors and
factors, this section will briefly highlight perinatal exercise as a positive intervention. For
more detailed reading on the impact of maternal exercise on offspring health, refer to the
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review by Blaize et al. [4].

Our laboratory has found that in mouse and rat models, maternal exercise (voluntary wheel
running vs. sedentary) significantly improves both insulin sensitivity and glucose
homeostasis in offspring [59,60]. Further, we found that male mice born to mothers that
exercised during pregnancy showed lower fat mass and greater lean mass compared to
offspring of sedentary pregnancies [59]. Additionally, maternal exercise during pregnancy

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conferred a protective effect in male rat offspring against non-alcoholic fatty liver disease in
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response to high fat diet [61]. We found that exercise during pregnancy can help stave off the
effects of the high fat diet on the pregnant dam herself [62]. Our findings from this study
showed that dams fed a high fat diet that were exercised showed comparable weight, glucose
disposal, and body fat mass with control sedentary mice fed a standard diet [62]. Since
diabetic and obese pregnancies can lead to negative traits in offspring (see sections 2.1.1–2),
this study suggests exercise during pregnancy may be an especially effective intervention in
obese pregnant women, although this needs to be tested in humans.

Other work has found a strong association between maternal exercise and improved
cardiovascular function in human and porcine offspring [63,64]. In humans, it was found
that maternal exercise was associated with increased fetal heart rate variability and
decreased heart rate, indicative of improved cardiac autonomic control [64]. In porcine
models, maternal exercise resulted in improved thoracic aorta endothelium-dependent
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vasorelaxation in female offspring [63]. Findings on maternal exercise in animal models are
not solely limited to metabolic or vascular programming; improvements in cancer risk and
Alzheimer’s risk in offspring have been observed as well [65,66].

These initial data in animal models indicate that prenatal exercise can lower the risk for age-
related diseases which could increase life expectancy, and further work in animals and
humans could delineate the specific mechanisms at work and underscore the importance of
maternal exercise as a positive intervention in offspring to increase health span and even life
span.

Conclusions
The growth of the developmental origins of health and disease field has opened new avenues
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for research and has led the scientific world to rethink traditional models of vertical
inheritance. It is evident from the above literature that a variety of perinatal influences can
have long lasting effects on traits which could affect health span and potentially increase or
reduce life expectancy in offspring. While we focused mainly on metabolic disease and
CVD risk, many studies on cancer and neurodegenerative disease can be found in the
literature.

This review asserts the importance of gestational health worldwide. With diabetic and obese
pregnancies common in the developed world and fetal malnutrition still common in
developing countries, it is extremely important for special emphasis to be placed on maternal
health. The vast and growing body of literature that examines the extreme sensitivity of the
maternal milieu and the perinatal period necessitates greater research effort and funding
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dedicated towards the developmental origins of health and disease hypothesis and
epigenetics. Moreover, an increase in large birth cohort studies involving (epi)genomic
testing would allow for an even greater body of knowledge in this field. Conclusive results
that elucidate the mechanisms at work in various developmental origins phenomena could
provide groundbreaking innovation in optimizing pregnancy feeding and exercise regimens,
creating pharmacogenomic interventions, and pinpointing both paternal and maternal
lifestyle adjustments that could have significant long-term effects on health span and life

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span in offspring. Studies reviewed in this article have shown promising temporary maternal
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interventions that help improve health in offspring. The treatment of maternal diabetes and
gestational diabetes mellitus, maternal smoking cessation, exercise interventions in obese
women who plan to become pregnant, and weight gain control during pregnancy all serve as
short-term interventions that can have long-term effects on offspring life span and health
span. A nine-month period serves as a relatively short investment of time in which
modifiable risks can be corrected and have exponentially larger effects on the health and
even life span of offspring.

Acknowledgments
K.J.P. was supported by US National Institutes of Health (NIH) grants (from the National Institute of
Environmental Health Sciences, P42ES007380, the National Institute of Diabetes and Digestive and Kidney
Diseases, R01DK090460, and the National Cancer Institute, R03CA165086). L.J.R. was supported by an American
Heart Association Post-Doctoral Fellowship (15POST25110002). We intended to include a brief overview of the
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literature in this wide-ranging field and apologize to any authors whose work was omitted.

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