Aging

Cardiovascular and Endocrine Systems

Similar to the general population, cardiovascular disease has become one of the leading causes of death in the SCI population (DeVivo et al. 1989; DeVivo et al. 1993; Frankel et al. 1998). There are multiple risk factors for its premature development due to physiological and functional changes following SCI (Bauman et al. 1994; Bauman & Spungen 2001a; Bauman & Spungen, 2001b). For instance, many age-associated disorders such as carbohydrate intolerance, insulin resistance (Duckworth et al. 1980; Duckworth et al. 1983; Bauman et al. 1992a; Karlsson 1999) and lipid abnormalities (LaPorte et al. 1983; Brenes et al. 1986; Bauman et al. 1992b; Bauman & Spungen 2001a) are known to occur prematurely in persons with SCI. Some have hypothesized that a marked decrease in physical activity (Myers et al. 2007), along with injury-related changes in metabolic function lead to an increased risk and premature development of cardiovascular disease (Bravo et al. 2004) and diabetes mellitus (Bauman et al.1992a).

Related to the metabolic changes noted above, there is a high prevalence of muscle weakness in persons with SCI attributed to a loss of lean body mass (Thompson & Yakura 2001) that is possibly linked to reduced activity, and abnormally low levels of endogenous anabolic hormones (i.e., human growth hormone and testosterone; Bauman et al. 1994). In the general population, age-related declines in the endocrine systems also lead to decreases in lean muscle mass and an increase in fat (Tenover 1999). However, these declines have been shown to be greater in persons with SCI (Bauman & Spungen 2001b). Similarly, noted changes in insulin resistance are thought to account for the high rates of diabetes mellitus in persons with SCI (Yekutiel et al. 1989). This in turn leads to an increased risk for cardiovascular disease since the development of diabetes impairs the circulatory system (Halter 1999). As such, it may be that alterations in body composition, which occur early following SCI, contribute to premature development of these disorders as compared to the AB population (Bauman et al. 1994). With some of the literature below, young adults with SCI are compared to young adults without SCI. Thus, aging effects due to SCI may be a factor when changes in the cardiovascular and endocrine systems occur in these young adults with SCI that would be typically expected to occur in older adults (e.g. characteristics associated heart disease such as poor lipid profiles, elevated glucose, high BMI). However, it is not always possible to disentangle mechanisms involving premature aging versus direct effects on the organs from the SCI itself.

Table 3. Cardiovascular and Endocrine Systems

Author Year; Country Score Research Design Total Sample Size	Methods	Outcome
Ho-Mu Wu et al. 2017; Taiwan Level 5 Cross-Sectional N = 71	Population: 71 people with SCI (61 M, 10 F) mean age (y)=36.4±11.7; mean TSI (months)= 87.5±106.4 (range 3-518); mean BMI (kg m^-2)= 22.8±4.2 High-level group (n=29), low-level group (n=42). Methodology: Participants were recruited from an outpatient clinic and they were grouped into either the high-level group (above T6) or the low-level group (below or at T6) to assess accelerated arterial stiffening in early years after SCI. Outcome Measures: Stiffness index (SI) and digital volume pulse (DVP) assessed using a photoelectric plethysmograph.	SI increased significantly with age, longer duration of SCI, higher BMI, and showed no differences regarding gender or level of injury The stiffening change of artery (vascular aging) accelerated in the early years of SCI, showing a logarithmic trend.
De Groot et al. 2016; The Netherlands Level 4 Retrospective review N = 223	Population: 87 people (75% M) with with SCI with MetS (metabolic syndrome) (39%): Mean age(y)=50.9±8.5, mean BMI(kg/m2)= 28.3±3.9, TSI (y)= 25.7±9.3, 84% motor complete, PASIPD (MET h/d)= 19.3±18.1, V̇O_2peak (mL/kg/min)= 15.6±5.1; 136 people (74 % M) with SCI without MetS: mean age (y)= 46.6±8.3, mean BMI (kg/m2)=23.5±3.7, TSI (y)=22.4±8.4, 79% motor complete, PASIPD(MET h/d)=20.9±23.2, V̇O_2peak (mL/kg/min)=17.6±6.7. Methodology: Participants were recruited from 8 Dutch rehabilitation centers (≥10 YPI) to study the prevalence of metabolic syndrome (MetS) in people with long-term SCI through a retrsospective chart review. Outcome Measures: Physical Activity Scale for Individuals with Physical Disabilities (PASIPD), BMI(kg/m2), graded wheelchair exercise test.	Both V̇O_2peakand PASIPD were not significantly associated with MetS. A 10-year increase in age led to a 1.5 times more chance to have MetS.
Hatchett et al. 2016; USA Level 2 Longitudinal N = 222	Population: 222 participants with SCI (198 M, 24 F); median age baseline (y) = 34.1; median duration of SCI (y) = 3.7 (range 2-20). Injury characteristics: AIS A (71%), AIS B (8%), AIS C (17%), AIS D (3%), high paraplegia (42%), low paraplegia (58%). Methodology: Researchers identified the prevalence of obesity in persons with chronic spinal cord injury (SCI), determined changes in body mass index (BMI) over time, and tracked distance travelled at baseline and 3 years. Outcome Measures: BMI at baseline and three years; WHO SCI adjusted BMI classification.	The median BMI over the three years was 24.2 kg/m2, and median body weight was 73.8 kg. Obese was the most common BMI category at baseline according to the SCI adjusted BMI classification (44%). 50% of paricipants maintained their weight within 5% of their BMI, 32% gained more than 5% of their BMI weight, and 18% lost more than 5% of their baseline BMI weight. Average velocity and distance propelled per day decreased in the group that increased their BMI over 3 years. BMI increased over the three year study with a median change in BMI of 0.46 kg/m2, and median change in weight of 1.4 kg.
Wecht et al. 2015; USA Level 5 Cross-sectional N_SCI=62 N_control=160	Population: 160 non-SCI veterans (mean age 57±11 years), 22 veterans with low thoracic SCI (mean age 57±10 years), 9 veterans with high thoracic SCI (mean age 48±20 years), 31 veterans with tetraplegia (mean age 60±11 years). Methodology: Assessments for the prevalence of heart rate and blood pressure abnormalities were completed to compare hemodynamic abnormalities between aging veterans with and without SCI. Outcome Measures: Prevalence of cardiac acceleration, orthostatic hypotension (OH), hypotension, and hypertension (HTN).	SCI status, but not AIS classification or duration of injury, contributed to the prevalence of cardiac acceleration and systolic and diastolic hypotension. OH did not differ among study groups.
Bauman et al. 2014; USA Level 3 SCI Cohort N=243	Population: 243 males with SCI; Mean age (years): 48±15 (range 21-78); Duration of injury (years): 17±13 (range 1-56) Testosterone (T) status: Low T n= 113, normal T n= 130; Level of injury: Paraplegia N=138, tetraplegia n=105 Completeness of Injury: Incomplete n=125, complete n=113 Methodology: All participants in the SCI cohort of this study had blood drawn between 8:00am-10:00am from the anticubital vein to determine serum T, albumin, and SHBG concentrations. The rate of decline T levels were compared a healthy male control population in the Massachusetts Male Aging Study. Normative data on men with low T levels were taken from the data of healthy men in the Baltimore Longitudinal Study on Aging. All cohorts were categorized into decades of life (20-29; 30-39; 40-49; 50-59; 60-69; 70-79) Outcome Measures: serum T (rate of decline, whether it is low), albumin, and SHBG concentrations.	The SCI group had a 50% greater decline in serum total T than that of the normative data in AB control group. There was a 13.1% annual increase of SHBG in men with SCI compared to 1.2% in the healthy general population For each decade of life (between 20-80 years), men with SCI had a 15, 39, 50, 53, 58, and 57% incidence rate of low serum total T concentration if determined for values of the serum total T concentration. For each decade of life (between 20-80 years) the incidence of hypogonadism was 4, 15, 28, 33, 56, and 76% by the free T index. Thus, for each decade of life, there was a substantial increase in the prevalence of low T in men with SCI compared to the historical general population sample Men with SCI who were <39 years old did not have an increased risk of low serum total T concentration, regardless of BMI and/or categorization for DOI. Men with SCI who were >40 years old had considerable increased likelihood of having a low serum total T concentration, dependent upon the categorization of BMI and/or DOI. Those who had higher BMIs (≥30 kg/m2) and longer DOI (≥25 years) had an odds ratio of having a low serum total T concentration of 8.9 times higher than those with the lower BMIs (<29.9 kg/m2) and shorter DOI (<24 years)
Lai et al. 2014; Taiwan Level 4 Retrospective review N_SCI= 52 420 N_non-SCI= 209 680	Population: All: 63.6% M, 36.5% F, mean age (y)=51.7±18.3. Methodology: To compare the incidence rate (IR) of Type 2 diabetes in SCI and non-SCI patients, data from Taiwan’s National Health Insurance Research Database between 1997-2010 were taken for patients ≥20 years old identified with SCI and included in the SCI cohort, while a non-SCI comparison cohort (around 5 non-SCI for every participant with SCI) was randomly age and sex matched. Age groups (y) were stratified into: 20-34; 35-44; 45-54; 55-64; 65+. Outcome Measures: Both cohorts were followed until the first of the following occurred: the diagnosis of Type 2 Diabetes, withdrawal form the insurance system, the end of 2010, or death.	The Insulin Resistance (IR) for diabetes in patients with and without SCIs was 22.1 per 10,000 person-years and 17.2 per 10,000 person-years, respectively. The adjusted hazard ratio (HR) for diabetes was 1.33 times higher in people with SCIs than in those without SCIs. People with SCIs, men, older people, those with comorbidities, and those with a complete thoracic SCI were more likely to be diagnosed with diabetes than other patient subgroups.
Ravensbergen et al. 2014; The Netherlands Level 2 Longitudinal N = 110	Population: 110 people with SCI (74.5% M): mean age (y)=44.1±13.3; Lesion level: cervical (36.4%), high thoracic (16.4%), low level (47.2%); Lesion completeness: AIS A (59.3%), AIS B,C,D (40.7%). Methodology: Participants were recruited from 8 Dutch rehab centers and were assessed 5 times. Cardiovascular variables were measured at the start of inpatient rehabilitation, 3 months later, at discharge, and at 1 and 5 years after discharge to study the prevalence and progression of cardiovascular dysfunction in people with SCI.	SAP did not significantly change over time. DAP did not change during the rehabilitation period but increased in the first 5 years after discharge. There was an interaction effect between time and lesion for SAP, but not for DAP. SAP decreased after discharge in those with cervical lesions but increased in those with low lesions. SAP increased by 3.6 mmHg and DAP increased by 1.7 mmHg for every 10-year increase in age HRrest decreased significantly during inpatient rehabilitation and decreased further from time of discharge to 5 years post-discharge. For every 10-year increase in age, HRpeak decreased by 10 BPM, though changes were insignificant.
Szlachcic et al. 2014; USA Level 2 Longitudinal N = 150	Population: 150 people with SCI (82.7% M, 17.3% F); mean age (y)=51.3 (range 35-77); mean duration of SCI at follow-up (y)=27.3 Methodology: A 17-year follow up of a convenience sample of 150 participants from a full cohort of 845 people with SCI who participated in a study previous between 1993-1997 was completed, with the average years to follow up being 15.7±0.9 years. The aim was to identify the magnitude of changes in biomarkers of and diabetes over time in people aging with SCI.	The frequency of cardiometabolic syndrome increased significantly from 6.7% (baseline) to 20.8% (17-year follow-up). It was significantly higher in Hispanics and apparently higher in women. Diabetes increased significantly by a factor of 6.7 from the baseline (3.3%) to 17-year follow up (22.2%). Respectively, BMI and waist circumference were moderately and significantly correlated with diabetes status at follow up.
de Groot et al. 2013; The Netherlands Prospective Longitudinal N=130	Population: 130 persons with SCI (91M 39F); mean (SD) age: 40.1(13.8) yrs. Methodology: Blood lipids and body mass index (BMI) were determined at discharge from inpatient rehabilitation and at 1 and 5 yrs after discharge; using multilevel regression models the effects of lifestyle (drinking alcohol, smoking, active lifestyle and self-care) on the lipid profiles and BMI were determined. Outcome Measures: Total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG),	After correction for lesion and personal characteristics, no changes in lipid profiles in the 5 yrs after discharge were seen, whereas BMI increased 1.8kgm^-2 between discharge and 5 years later A high percentage was at risk of cardiovascular disease after 5 yrs due to high BMI (63-75%) or HDL (66-95%). The percentage at risk of other unfavorable lipid levels was lower (3-35%). Age was significantly and unfavorably related to total cholesterol, low-density lipoprotein, triglycerides and BMI. Individuals who indicated they maintained their fitness level and individuals with low BMI showed better lipid profiles. Individuals with a more active lifestyle showed higher HDL levels, but individuals, who “often or always avoid(ed) smoking” had a 1.5kgm^-2 higher BMI.
Hosier et al. 2012; USA Cross-sectional Level 5 N=17	Population: 17 women with SCI; Premenopausal group (n=11): mean (SD) age in yrs: 32.4 (10); 1 tetraplegia, 11 paraplegia; AIS: AIS A n=5, AIS B n=6 Postmenopausal group (n=6): mean (SD) age in yrs: 56.0 (9.4); 3 tetraplegia, 3 paraplegia; AIS: AIS A n=4, AIS B n=2; Age at menopause (yrs): mean 43.8. Methodology: Participants were stratified into 2 groups according to menopausal status. Outcome Measures: Fasting serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), calculated low-density lipoprotein (LDL-C), fasting blood glucose (FBG), systolic blood pressure (SBP).	Groups were similar on BMI (22.4 vs. 22.2), HDL-C (52.5 vs. 53 mg/dL), FBG (79.3 vs. 84.8 mg/dL), and SBP (104.6 vs. 111.8 mm Hg). TG, TC and LDL-C were significantly higher in post-menopausal group (55.7 vs. 101.8 mg/dL; 158.3 vs. 191.6 mg/dL; 94.7 vs. 118.2 mg/dL).
de Groot et al. 2010; The Netherlands Longitudinal N=184	Population: 184 persons with SCI (138M 46F); mean(SD) age 40.2(14.1) yrs; mean(SD) time since injury 94.8(65.8) days; 61% paraplegia, 70% complete lesion. Methodology: BMI was determined at the start of active rehabilitation, 3 months later, at discharge, and 1, 2, and 5 yrs after discharge. Outcome Measures: BMI.	BMI did not significantly increase during inpatient rehabilitation, but showed a significant increase the year after discharge. BMI increased by 1 kg/m² for each 10-year increase in age.
Liang et al. 2007; USA Cross-sectional with AB controls N SCI=185 N controls=185	Population: 185 men with SCI, mean(SD) age 39(10.4) yrs; mean YPI 11.7 (range 1-40.4 yrs); age, gender, and race-matched AB controls. Methodology: Comparison of prevalence rates of metabolic syndrome. Outcome Measures: Total cholesterol (TC), HDL and LDL; Elevated glucose; Triglyceride (TG).	Group with SCI had decreased levels of all of the followings: HDL, TG, glucose, TC, and LDL. Characteristics of metabolic syndrome (a condition associated with aging) were more prevalent in young SCI individuals than controls.
Orazaki et al. 2007; USA Cross-sectional with AB controls N SCI=82 N controls=273	Population: 82 participants with SCI (67M 15F); mean(SD) age 49.7(12) (range 20-90 yrs), mean(SD) YPI 19.7(10); 273 age, gender, ethnicity, and risk factor-matched AB controls. Methodology: Comparison of the burden of atherosclerosis between SCI and control groups. Outcome Measures: Coronary artery calcium (CAC) scores, mean calcium scores.	CAC was greater in persons with SCI than in AB controls Atheroselerosis, a condition related to aging was more prevalent in SCI.
Wang et al. 2007; Taiwan Cross-sectional with AB controls N SCI=62 N controls=29	Population: 62 males with complete SCI; mean(SD) age 28.0(9.7) yrs (range 16.2–59.1 yrs); mean(SD) YPI 11.8(7.0) (1.2–27.7 yrs); age- and gender-matched AB controls. Methodology: Comparison of serum levels of markers of inflammation and endothelial activation between SCI and controls. Outcome Measures: Body weight, BMI, serum levels of albumin, creatinine, LDL, HDL, insulin, C-reactive proteins (CRP), interleukin-6, endothelin-1, and sVCAm-1.	Compared to AB controls, group with SCI had significantly lower body weight and BMI, as well as lower serum albumin and creatinine levels. Group with SCI had lower levels of density lipoprotein-cholesterol (LDL), lower levels of high-density lipoprotein-cholesterol (HDL), and an increased total cholesterol/HDL cholesterol ratio, and a trend toward increased insulin levels than AB controls. Group with SCI had increased serum levels of CRP, interleukin-6, endothelin-1, and sVCAm-1 than AB group.
LaVela et al. 2006; USA Cross-sectional with AB controls N SCI = 3708 N controls = 18018	Population: 741 veterans (98.2% male) with SCI disorder (e.g., traumatic injury, multiple sclerosis), mean age 64.1 (range < 40 to 70+ yrs); mean YPI 23.9 yrs; 2,967 veterans with SCI/D (96.8%) and no diabetes; mean age 59.2 yrs, mean YPI 23.8 yrs; 1342 veteran AB controls (age range <40 – >70 yrs) and 16676 general population AB controls (age range <40 – >70 yrs). Methodology: Comparison of prevalence rates of diabetes mellitus. Outcome Measures: Prevalence of diabetes.	Diabetes prevalence increased among veterans with SCI disorders compared to general population, but similar to other veterans. For those 45 to 59 yrs of age, diabetes prevalence was increased in veterans with an SCI/D.
Bauman et al. 2004; USA Cross-sectional with AB controls N SCI=13 N controls=13	Population: 13 men with SCI, mean(SD) age 37(8) yrs; mean(SD) YPI 15(9); AB identical twins of participants were control. Methodology: Comparison of energy expenditure and fat-free mass (FFM) with monozygotic twin. Outcome Measures: Basal energy expenditure (BEE) and resting energy expenditure (REE) by indirect calorimetry; Fat-free mass (FFM) and fat mass (FM) assessed by dual-energy X-ray absorptiometry; Total body potassium (TBK).	Twin with SCI had decreased BEE and REE compared to AB twin. Fat mass was equivalent between groups, but ratios of FM to FFM and FM to TBK were decreased in twins with SCI.
Jones et al. 2004; New Zealand Cross-sectional with AB controls N SCI=20 N controls=20	Population: 20 men with SCI, mean(SD) age 33(2) (range 16-52 yrs); mean(SD) YPI 10.3(1.8) yrs; 20 age, gender, height, weight, and activity level-matched AB controls. Methodology: Comparison of prevalence of metabolic syndrome (i.e., symptoms that increase cardiovascular risk such as high blood pressure and glucose levels). Outcome Measures: Lean and fat mass; Plasma glucose and insulin; Total cholesterol; HDL; Oral glucose tolerance test (OGTT).	55% of the group with SCI met the criteria for metabolic syndrome, whereas none of the controls did.
Jones et al. 2003; New Zealand Cross-sectional with AB controls N SCI=19 N controls=19	Population: 19 men with SCI; mean(SD) age 34(8) (range 16-52 yrs); mean YPI > 1 yr; age, gender, height, and weight-matched AB controls. Methodology: Comparison of BMI and adiposity. Outcome Measures: BMI; Total body and regional lean tissue and fat mass.	BMI was similar in both groups but total body lean tissue mass was decreased and total body fat mass was increased in the SCI group. Body fat percentage was increased in group with SCI.
Petrofsky & Laymon 2002; USA Cross-sectional with AB controls N SCI=50 N controls=50	Population: 50 men with complete paraplegia, divided into four age groups (20 – 30 yrs, 31 – 40 yrs, 41 – 50 yrs, 51 – 65 yrs); YPI range 3 – 10 yrs; age-, gender-, and height-matched AB controls. Methodology: Comparison of blood pressure and heart rate during isometric exercise and at rest (leg and arms). Outcome Measures: Heart rate, blood pressure.	Group with SCI had a larger change in blood pressures both at rest and during leg exercise. Heart rate during handgrip exercise was normal for both SCI and AB groups, but was absent in the SCI group during the leg exercise.
Bauman et al. 2001; USA Cross-sectional with AB controls N SCI=835 N controls=14,838	Population: 835 participants with SCI (723M 122F); mean(SD) age 38(11) yrs, mean(SD) YPI 12(9). Methodology: Comparison of levels of plasma homocysteine to AB reference population. Outcome Measures: Plasma homocysteine (PH).	Older group with SCI (>50 yrs) had increased mean PH than the younger age group. Group with SCI had increased levels of PH compared to the control group. SCI group had elevated plasma homocysteine which is associated with an increased risk of vascular disease.
Demirel et al. 2001; Turkey Cross-sectional with AB controls N SCI=69 N controls=52	Population: 69 participants with SCI (53M 16F); mean(SD) age 33.9(11.37) yrs (range 10–70); mean(SD) YPI 16(10) (range 1–41); age- and gender-matched AB controls. Methodology: Comparison of standard risk factors for coronary heart disease (CHD). Outcome Measures: BMI, blood pressure, diabetes mellitus, HDL, LDL, total cholesterol.	Impaired fasting glucose, diabetes mellitus, hyperuricemia, high total cholesterol (TC), low density lipoprotein-cholesterol (LDL), low high-density lipoprotein-cholesterol (HDL), high TC/HDL, LDL/HDL ratios were more common in persons with SCI than in the AB group.
Spungen et al. 2000; USA Cross-sectional with AB controls N SCI=8 N controls=8	Population: AB twins of 8 males with SCI with complete paraplegia, mean(SD) ages 40.4(10) yrs, mean(SD) YPI 16(9) yrs. Methodology: SCI participants were compared with twin on total and regional lean tissue and fat mass. Outcome Measures: Body composition.	Group with SCI had significant decrease in total body lean mass compared to AB twin group, independent of age. Group with SCI had significantly increased total body fat mass compared to AB twin group.
Bauman et al. 1999; USA Cross-sectional with AB controls N SCI=320 N controls=303	Population: 320 participants with SCI (234M 86F); mean (SD) age 41(0.62) yrs (range 20-77), mean (SD) YPI 15(0.52) (range 1-57 yrs); 303 age-, gender-, ethnicity-, and activity level-matched AB controls. Methodology: Comparison of serum lipid profiles between SCI and controls. Outcome Measures: Serum levels: total cholesterol (TC), triglycerides (TG), HDL-cholesterol (HDL-c), LDL-cholesterol (LDL-c), body mass index (BMI).	Group with SCI had decreased levels of TC, TG, HDL-c and LDL-c, and increased levels of TC/HDL-c ratio compared to the AB control group. The AB control group had increased BMI compared to the group with SCI, but the estimated per cent body fat was increased in the group with SCI.
Yamamoto et al. 1999; Japan Cross-sectional with AB controls N SCI=7 N controls=7	Population: 7 men with complete tetraplegia; mean(SD) age 41(10.0) (range 33–58 yrs); mean(SD) YPI 13.7(3.4) (range 9–18 yrs); age- and gender matched AB controls (n=7). Methodology: Comparison of blood pressure, heart rate, and hormonal changes during 2 minutes of sustained contraction. Outcome Measures: Heart rate, blood pressure.	Group with SCI had no changes in heart rate during exercise, whereas AB controls did change. Blood pressure increased in both groups.
Apstein & George 1998; USA Longitudinal with AB controls N SCI=100 N controls=80	Population: 100 men with SCI, mean age 45; 80 age- and gender-matched AB controls. Methodology: Evaluate changes in serum lipids at 4, 16, 36 and 52 weeks post-injury, and compared at 52 weeks compared to AB controls. Outcome Measures: Serum levels of total cholesterol (TC), LDL, HDL.	Total serum cholesterol (TC) levels were always decreased in males with tetraplegia compared to males with paraplegia. No differences in triglycerides between SCI groups at any time. At 4 weeks after injury, low-density lipoprotein-cholesterol (LDL) were decreased in males with tetraplegia compared to males with paraplegia, but were equivalent at 1 YPI. Serum high-density lipoprotein cholesterol (HDL) were decreased in the group with tetraplegia compared to group with paraplegia at 4 weeks, but increased compared to AB levels at 1 YPI. LDL/HDL ratio was lower at 4 weeks to 1 YPI in the group with tetraplegia compared to group with paraplegia, whose LDL/HDL was comparable to AB controls.
Huang et al. 1998; China Cross-sectional with AB controls N SCI=25 N controls=25	Population: 25 men with SCI; mean age 35.4 (range 18-55 yrs); mean YPI 7.5 (range 1.1-15.8 yrs); age and gender matched AB controls. Methodology: Comparison of hypothalamus-pituitary-adrenal axis. Outcome Measures: Radioimmunoassay methods, corticotropin-releasing hormone levels.	Cortisol response to corticotropin-releasing hormone was decreased in SCI group, but differences disappeared if correction was made for baseline values.
Bauman et al. 1996; USA Cross-sectional with AB controls N SCI=34 N controls=48	Population: 34 males with SCI, mean(SD) age 50(2) yrs, mean(SD) YPI 11(2); 48 age- and gender-matched AB controls. Methodology: Comparison of Body Mass Index (BMI) and plasma leptin (PL) between SCI and control groups. Outcome Measures: Plasma leptin levels, BMI.	Group with SCI had increased levels of PL compared to the control group. No significant differences in BMI between SCI and control groups.
Cheville & Kirshblum 1995; USA Cross-sectional with AB controls N SCI=30 N control=30	Population: 30 participants with SCI (29M 1F); mean age 59 (range 22-82 yrs); mean YPI 24 (range 2-50 yrs); age and gender-matched AB controls. Methodology: Comparison of thyroid function and to determine the incidence and clinical prevalence of low T3 syndrome. Outcome Measures: Serum levels of triiodothyronine (T3) and thyroxin (T4).	Mean triiodothyronine (T3) levels and thyroxin (T4) levels were significantly decreased in the group with SCI. T3 resin uptake levels (measure of serum thyroid hormone) were significantly increased in the group with SCI. Altered thyroid function was found in the SCI group.
Tsitouras et al. 1995; USA Cross-sectional with AB controls N SCI=20 N controls=16	Population: 20 men with SCI, mean(SD) age 42(2) yrs, mean(SD) YPI 15(2); 16 healthy males, mean(SD) age 39(4) yrs. Methodology: Comparison of serum growth hormone and testosterone between the 2 groups. Outcome Measures: Serum testosterone (T), human growth hormone (hGH) and insulin-like growth factor 1 (IGF-I).	SCI is associated with impaired secretion of both T and hGH (not the result of aging). Time since injury appears to have an adverse effect on serum T.
Bauman et al. 1994; USA Cross-sectional with AB controls N SCI=16 N controls=16	Population: 16 men with SCI; mean(SD) age 45(3) yrs, mean(SD) YPI 19(3); 16 controls mean(SD) age 39(4) yrs. Methodology: Comparison of growth hormone response to intravenous infusion of arginine hydrochloride (30 g/subject over 30 minutes). Outcome Measures: Plasma human growth hormone (hGH) release and plasma insulin-like growth factor (IGF-I) levels; Body Mass Index (BMI).	Mean hGH responses at 30 and 60 minutes were significantly decreased in the group with SCI than in the control group (3.4(0.7) vs. 10.7(2.5) ng/ml; and 5.2(1.5) vs. 12.5(2.7) ng/ml), even when controlled for age and BMI. Mean plasma IGF-I levels were decreased in SCI participants <45 years old than in AB counterparts (202(19) vs. 324(27) ng/ml). Comparison of those >45 years old revealed no differences. Lower daily physical activity depresses hGH/IGF-I axis in younger individuals with SCI and may be considered a state of premature aging.
Bauman & Spungen 1994; USA Case-control Level 3 N SCI=100 N controls=50	Population: 50 men with paraplegia (mean(SD) age 51(2) yrs, mean(SD) YPI 19(2)) and 50 men with tetraplegia (mean(SD) age 47(2) yrs, mean(SD) YPI 17(2)); 50 male controls (mean(SD) age 51(2) yrs). Age- and Body Mass Index (BMI)-matched. Methodology: Comparison of responses from oral glucose tolerance test (OGTT). Outcome Measures: Mean plasma glucose and insulin values, serum lipid levels.	82% of controls had normal oral glucose tolerance vs. 38% of those with tetraplegia and 50% with paraplegia. 22% of SCI group were diabetic vs. 6% of controls. Those with SCI develop carbohydrate disorders at younger ages. Participants with SCI had significantly higher mean glucose and insulin values during the OGTT when compared to controls. Serum lipid levels in participants with SCI showed a decreased HDL cholesterol level (38(1) mg/dL).
Huang et al. 1993; China Case-control Level 3 N SCI=30 N controls=30	Population: 30 men with SCI, ages 17.4 – 43.9 yrs, mean 31.4 yrs; 30 healthy males, ages 21.0 – 38.7 yrs, mean 29.6 yrs. Methodology: Comparison of pituitary-testicular and pituitary-thyroid axes with age matched, sexually active control population. Outcome Measures: Endocrinologic studies, Radioimmunoassay methods.	4 persons with SCI had low levels of serum triiodothyronin (i.e., altered thyroid metabolism), 1 with increased serum follicle-stimulating hormone, 8 with increased serum testosterone levels, and 11 with increased serum prolactin levels. Compared to AB controls, persons with SCI had increased luteinizing hormone (LH) responses (hormone from pituitary gland), with 8 having exaggerated or prolonged LH responses.
Leaf et al. 1993; USA Longitudinal Level 2 N SCI=47	Population: 22 participants with tetraplegia (mean(SD) age 39.0(16.7), range 15-80 yrs); 25 persons with paraplegia, (mean(SD) age 42.0(18.8), range 19-82 yrs); YPI range for both groups 35-3605 days. Methodology: Characterize the risk of cardiac dysrhythmias via 24 hrs Holter monitoring, and to determine if significant cardiac event occurred at 2 yrs post-baseline. Outcome Measures: Holter monitoring.	Despite the theoretical basis for increased incidence of cardiac dysrhythmias following SCI, no significant cardiac events occurred for sample at 2 yr follow-up.
Shetty et al. 1993; USA Case-control Level 3 N SCI=41 N controls=119	Population: 41 men with tetraplegia, mean age 41 yrs (range 24-66 yrs); 119 AB control, age range 30-70 yrs. Methodology: Comparison of growth hormone (GH) and Somatomedin C (SmC) concentrations in the two groups. Outcome Measures: Radioimmunoassay of SmC.	SmC was decreased in the group with SCI than AB controls. Inverse relationship between SmC level and increasing age in both groups. Severe inactivity or SCI may cause hyposomatomedinemia, which could contribute to decreased lean body mass and muscle atrophy, increased risk for pressure sore formation and osteoporosis post-SCI.
Wang et al. 1992; China Case-control Level 3 N SCI=63	Population: 63 men with SCI; mean age 31.2 (range 18-44 yrs); mean YPI 6.2 (range 8 mos-20 yrs); AB reference population. Methodology: Comparison of hormone patterns of gonadotropin and testosterone. Outcome Measures: Serum levels of triiodothyronine, testosterone, serumfollicle-stimulating hormone, luteinizing hormone.	7 persons with SCI had decreased serum triiodothyronine below reference level, and 8 people had low serum testosterone. 17 persons with SCI had hyperprolactinemia, and 9 cases had elevated serum testosterone level. 6 persons with SCI had elevated serumfollicle-stimulating hormone and 4 cases had elevated luteinizing hormone.
Zlotolow et al. 1992; USA Case-control Level 3 N SCI=28 N controls=52	Population: 28 men with paraplegia, mean(SD) age 48(2) yrs (range 25-65 yrs); YPI ≥1.5 yrs; 52 age- and gender-matched AB controls. Methodology: Comparison of diet, BMI, and serum lipid levels between SCI and AB control groups. Outcome Measures: Serum levels of total cholesterol, HDL, and triglycerides; total caloric and cholesterol intake from diet; BMI.	No differences in BMI, total caloric or cholesterol intake between SCI and AB control groups. Serum HDL cholesterol levels decreased compared to AB controls. Total caloric intake decreased with age in AB controls but not SCI group.
Nuhlicek et al 1988; China Case-control Level 3 N SCI=37 N controls=10	Population: 37 men with SCI; 19 with tetraplegia; 18 with paraplegia; age range 19-49 yrs; age and gender matched AB controls. Methodology: Comparison of body composition between control and groups of different SCI injury levels. Outcome Measures: Anthropometry; Total body water (TBW); Predicted extracellular water (ECW); Lean body mass (LBM) and body cell mass (BCM); Extracellular mass (ECM) and extracellular water (ECW).	Diminishing TBW, LBM, BCM, and muscle cell mass, and increasing fat mass with higher spinal lesions. No change in total body weight, ECM or ECW.

Discussion

Cardiovascular System

In this section, the evidence reviewed appears to support the notion that the cardiovascular system is prematurely aging. With regard to risk factors for cardiovascular disease, Bauman and colleagues (2001a) found that regardless of age or sex, persons with SCI had significantly higher levels of plasma homocysteine than able bodied (AB) controls, and that older persons with SCI (>50 years) had higher levels than younger persons with SCI. Plasma homocysteine is thought to promote coagulation and to decrease the resistance of the endothelium to thrombosis (Malinow 1994), and is a clear independent marker for the prediction of vascular disease (Clarke et al. 1991; Stampfer et al. 1992). The findings regarding lipid profiles also support an increased risk for the development of cardiovascular disease. Several studies (Demirel et al. 2001; Zlotolow et al. 1992; Bauman & Spungen 1994; Bauman et al. 1995; Bauman et al. 1999; Liang et al. 2007; Wang et al. 2007) found that serum high-density lipoprotein cholesterol (HDL-c) are depressed in persons with SCI compared to AB controls, which is associated with an increased risk for developing coronary heart disease (Goldbour & Medalie 1979; Castelli 1984).

An important factor influencing these variables might be lifestyle. For instance, one longitudinal study (Shiba et al. 2010) on athletes with SCI (N = 7) found that physical capacity was maintained over a span of two decades. The results of this study, however, are limited to individuals participating in strenuous sport activities, a sample that is not representative of the general SCI population (Maki et al. 1995). Although no blood pressure changes were noted, the sample did have a significantly higher BMI from baseline to 20-year follow-up. Unfortunately, data on lipid profiles were not collected in this study. Further work on the role of diet and physical activity is needed to help clarify their impact on aging with SCI.

One study provides evidence that C-reactive protein levels were higher in men with SCI (N = 62) compared to AB controls (N = 29), which could also account for the decreases in total cholesterol, low-density lipoprotein and high-density lipoprotein. At the same time, increases in C-reactive protein levels may also partly explain why persons with SCI are nonetheless at increased risk for accelerated atherogenesis (Wang et al. 2007). A risk factor for vascular disease in both symptomatic (Budoff et al. 2005) and asymptomatic (Raggi 2000) populations is coronary artery calcification (CAC), which is a component of atherosclerotic plaque. Orakzai and colleagues (2007) found significantly higher levels of CAC in persons with SCI (N = 82) compared to AB controls (N = 273), and that the risk was higher for males and for persons with tetraplegia.

Sustaining a SCI also affects blood pressure by altering the sympathetic activity to blood vessels. There is evidence that men with tetraplegia (Yamamoto et al. 1999) and paraplegia (Petrofsky & Laymon 2002) have increased blood pressure responses during exercise compared to AB controls. As well, Petrofsky and Laymon (2002) found that their group with paraplegia had a larger change in blood pressure both at rest and during exercise and was more associated with aging than for the controls. Disturbingly, static exercise has been found to cause tachycardia in AB controls, but not in persons with SCI (Petrofsky & Laymon 2002; Orakzai et al. 2007) when paralyzed muscles were engaged. Several studies highlight that irregular blood pressure responses post-SCI have significant implications for cardiovascular health (Bluvshtein et al. 2011; Groothuis et al. 2010a; Groothuis et al. 2010b; La Fountaine et al. 2010; Yasar et al. 2010). Overall, these findings are indicative of altered autonomic control, but not necessarily of aging. Further work is needed to determine the long-term implications for cardiovascular health.

Decreases in physical activity may contribute to the development of cardiovascular disease, which may be reflected in body composition changes following SCI. Two longitudinal studies from the same author (de Groot et al. 2010; 2013) found that body mass index (BMI) increases over time in individuals with SCI. In the de Groot et al. (2010) study of 184 individuals, BMI was observed to significantly increase the year after discharge from in-patient rehabilitation. In the de Groot et al. (2013) study of 130 individuals, BMI was observed to increase from discharge to a 5-year follow up. Individuals in this study, however, showed no change in their lipid profie over the 5 years of observation. Similar BMI findings have been reported by Crane and colleagues (Crane et al. 2011). However, studies comparing BMI between individuals with SCI and AB individuals have demonstrated mixed results. One study (Spungen et al. 2000) found greater BMI levels in persons with SCI compared to AB controls, whereas other studies found the opposite (Bauman et al. 1999; Bauman et al. 2004; Wang et al. 2007), or no differences at all (Zlotolow et al. 1992; Jones et al. 2003; Bauman et al. 1996).

Given these contradictory findings, BMI may not be an appropriate measure for SCI since studies that also examined lean and fat mass tissue (Bauman et al. 1996; Bauman et al. 1999; Spungen et al. 2000; Bauman et al. 2004; Jones et al. 2004) found that persons with SCI had significantly higher levels of fat mass tissue and lower levels of lean tissue than AB controls. These differences in lean and fat mass tissue appear to be attributable to YPI, and not age. For instance, Spungen et al. (2000) found lower lean mass and higher fat mass in persons with SCI who were matched with their AB monozygotic twin, which was directly related to YPI. As well, Bauman and colleagues (2004) concluded from their monozygotic SCI twin study that reductions in lean muscle tissue lead to reduced energy expenditure, which appeared to be related – albeit not significantly – to YPI. These findings are congruent with SCI-only cross-sectional studies examining body composition (Cardus & McTaggart 1985; Shizgal et al. 1986; Rossier et al. 1991).

The findings from a cross sectional study (Hosier et al. 2012) comparing cardiometabolic risk profiles in pre and post-menopausal women reported that post-menopausal women with SCI have higher triglycerides, total cholesterol, and low density lipoprotein than pre-menopausal women. No differences were observed in BMI or glycemic indices. The authors suggest that post-menopaual women with SCI have risk profiles that are similar to those observed in women without SCI, characterized by increases in triglycerides, total cholesterol, and low density lipoprotein, despite favorable BMIs and glycemic indices.

Endocrine System

Metabolic changes after SCI may also be associated with changes in body composition, and may increase the risk of developing diabetes mellitus. Tsitouras and colleagues (1995) posited that impaired hGH secretion may be partially responsible for SCI- and aging-associated lean body and muscle mass depletion. Several identified studies (Shetty et al. 1993; Bauman et al. 1994; Tsitouras et al. 1995) provide evidence that serum IGF-I levels are lower in persons with SCI compared to age-matched controls, and that this depletion is associated with impaired hGH. Bauman et al. (1994) found that the average IGF-I was significantly lower in younger individuals with SCI than that in younger AB controls, but not in those greater than 45 years of age. As such, this pattern of IGF-I levels in younger males with SCI appears to be similar to those of elderly AB individuals (Bauman et al. 1994).

Related to this, Bauman and Spungen (1994) found that persons with SCI had a higher mean glucose and insulin levels, and lower mean fasting plasma glucose levels than the AB control group. This intolerance was found to be present in two-thirds of their group with tetraplegia, and in half their group with paraplegia. Further, 22% of the persons with SCI met the diagnostic criteria for having diabetes mellitus, whereas only 6% of the AB controls were found to be diabtetic. Since these adverse clinical features occurred at younger ages in their SCI sample, Bauman and Spungen (1994) interpreted their findings as being a model of premature aging. The findings of Jones and colleagues (2004), and LaVela and colleagues (2006) appear to support this hypothesis as they both found higher rates of metabolic syndrome and diabetes in their SCI samples compared to the AB population. Conversely, Liang et al. (2007) found that males with SCI (N = 185) were not at higher risk for metabolic syndrome compared to AB controls (N = 185). This discrepancy may be due to some of the study’s limitations (i.e. reliance on self-report height and weight to calculate BMI) and because they used a standard, rather than a modified, criteria for the syndrome which is not appropriate for persons with SCI.

The predisposition to diabetes and lipid abnormalities is thought to be largely a consequence of extreme inactivity, and the constellation of metabolic changes (i.e. human growth hormone deficiency, testosterone deficiency) appears to be occurring prematurely in persons with SCI (Bauman & Spungen 1994). As well, several studies have shown evidence of thyroid impairment after SCI compared to the AB population (Wang et al. 1992; Huang et al. 1993; Cheville & Kirshblum 1995).All of these findings suggest that persons with SCI may be frequently physiologically comprised, and more susceptible to minor pathologic insults. Along with associated changes in body composition, an increased risk for the development of cardiovascular disease, diabetes mellitus, and infection is higher following SCI (Bauman & Spungen 2001b).

Conclusion

There is Level 5 evidence from one cross-sectional study (Bauman & Spungen 2001a) that plasma homocysteine levels are higher in persons with SCI compared to the AB population, with the greatest discrepancy in older adults with SCI (> 50 years).

There is Level 5 evidence from nine cross-sectional studies (Zlotolow et al. 1992; Huang et al. 1993; Bauman & Spungen 1994; Bauman et al. 1996; Huang et al. 1998; Bauman et al. 1999; Demirel et al. 2001; Liang et al. 2007; Wang et al. 2007) that lipid profiles are altered after SCI which may contribute to the development of cardiovascular disease.

There is Level 4 evidence (Shiba et al. 2010) that physical capacity can be maintained long-term in male athletes with SCI.

There is Level 4 evidence from one longitudinal study (de Groot et al. 2013) that lipid profiles in adults with SCI remain stable during the 5 years after inpatient rehabilitation.

There is Level 4 evidence (Apstein & George 1998) that total cholesterol (TC), total glycerides (TG), and low-density lipoproteins (LDL) increased while LDL/high-density lipoproteins (HDL) ratios decreased for males with tetraplegia and paraplegia from the acute phase until 1 YPI. All lipid profiles were significantly depressed compared to controls.

There is Level 4 evidence (Apstein & George 1998) that persons with tetraplegia had low HDL and elevated LDL/HDL ratios, which places them at an increased risk for coronary artery disease.

There is Level 5 evidence (Wang et al. 2007) that C-reactive protein levels are higher in males with SCI, which could also account for the decreases in TC, LDL, and HDL. Elevated C-reactive protein levels may also partly explain why persons with SCI are at increased risk for accelerated atherogenesis.

There is Level 5 evidence (Orakzai et al. 2007) that persons with SCI have greater atherosclerotic burden compared to an AB reference population.

There is Level 5 evidence from two studies that men with complete paraplegia (Petrofsky & Laymon 2002) and with complete Tetraplgia (Yamamoto et al. 1999) have an abnormal (absent) heart rate response to isometric exercise.

There is Level 5 evidence that men with complete tetraplegia demonstrate increased blood pressure (Yamamoto et al. 1999) response to isometric contraction.

There is Level 5 evidence (Wang et al. 1992: 63 men; Tsitouras et al. 1995; Shetty et al. 1993) that there is lower secretion of testosterone and human growth hormone levels in men with SCI compared to AB controls.

There is Level 5 evidence from two studies (Tsitouras et al. 1995; Bauman et al. 1994) that serum IGF-I levels are impaired in persons with SCI compared to the AB population, which may be a sign of premature aging.

There is Level 5 evidence from three studies (Bauman & Spungen 1994; Jones et al. 2004; Liang et al. 2007) that glucose tolerance is impaired after SCI, which may lead to an increased risk for premature diabetes mellitus.

There is Level 5 evidence (LaVela et al. 2006) that diabetes mellitus occurs prematurely in male veterans with SCI compared to AB individuals in the general population, but not veteran controls.

There is Level 5 evidence (Lewis et al. 2010) that men with SCI have slower plasma-free cortisol responses than AB controls.

There is Level 4 evidence from three longitudinal studies (de Groot et al. 2010 & 2013; Crane et al. 2011) that BMI increases significantly over time in persons with SCI.

Seven studies (Nuhlicek et al. 1988 ; Bauman et al. 1996 ; Bauman et al. 1999 ; Spungen et al. 2000 ; Jones et al. 2003 ; Jones et al. 2004; Emmons et al. 2011) provide Level 5 evidence that persons with SCI are likely to have higher levels of fat mass, and that age-related declines of lean tissue in males with SCI may occur at a significantly faster rate than the AB population.

There is Level 5 evidence from one monozygotic twin study (Bauman et al. 2004) that basal and resting energy expenditures are lower in males with SCI compared to their AB twin.

There is Level 5 evidence from one cross-sectional study (Hosier et al. 2012) that post-menopaual women with SCI have cardiometabolic risk profiles that are similar to those observed in women without SCI.

Greater levels of arthersclerotic burden, higher levels of C-reactive protein levels and abnormal lipid profiles compared to the able-bodied population increases the risk for the development of cardiovascular disease in persons with SCI.

Men with complete SCI have abnormal heart rate and blood pressure responses to isometric exercise compared to able-bodied controls, which are indicative of altered autonomic control, but this may not represent premature aging.

Impaired secretion of both testosterone and human growth hormone in men with SCI may be due to SCI, and not from advancing age per se.

Serum IGF-I levels may be impaired compared to the able-bodied population, which may be a sign of premature aging.

Glucose tolerance and slower plasma-free cortisol responsesmay be impaired in persons with SCI, which may lead to an increased risk for premature diabetes mellitus.

Persons with SCI are at higher risk for the development of cardiovascular disease and diabetes mellitus than the able-bodied population.

Persons with SCI may have higher levels of fat mass than the able-bodied population. Although BMI increases over time in people with SCI, an active lifestyle may help to preserve physical capacity.

Age-related declines of lean tissue in males with SCI may occur at a significantly faster rate than the able-bodied population.

Age of onset may not influence hematologic abnormalities at the acute phase post-SCI (within first week post-injury).